Pathway-Directed Therapy in Multiple Myeloma
Abstract
:Simple Summary
Abstract
1. Introduction
2. RAS/RAF/MEK/ERK-Pathway Directed Therapies
3. PI3K/AKT-Pathway-Directed Therapies
3.1. AKT
3.2. MTOR
4. PIM-Directed Therapies
5. Transcription Factor-Directed Therapies
5.1. C-MYC Directed Therapies
5.2. p53 Directed Therapies
5.3. Other TF-Directed Therapies
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Sant, M.; Allemani, C.; Tereanu, C.; De Angelis, R.; Capocaccia, R.; Visser, O.; Marcos-Gragera, R.; Maynadié, M.; Simonetti, A.; Lutz, J.M.; et al. Incidence of hematologic malignancies in Europe by morphologic subtype: Results of the HAEMACARE project. Blood 2010, 116, 3724–3734. [Google Scholar] [CrossRef] [PubMed]
- Rajkumar, S.V.; Dimopoulos, M.A.; Palumbo, A.; Blade, J.; Merlini, G.; Mateos, M.V.; Kumar, S.; Hillengass, J.; Kastritis, E.; Richardson, P.; et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014, 15, e538–e548. [Google Scholar] [CrossRef]
- McCarthy, P.L.; Holstein, S.A.; Petrucci, M.T.; Richardson, P.G.; Hulin, C.; Tosi, P.; Bringhen, S.; Musto, P.; Anderson, K.C.; Caillot, D.; et al. Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis. J. Clin. Oncol. 2017, 35, 3279–3289. [Google Scholar] [CrossRef] [PubMed]
- Dimopoulos, M.A.; Dytfeld, D.; Grosicki, S.; Moreau, P.; Takezako, N.; Hori, M.; Leleu, X.; LeBlanc, R.; Suzuki, K.; Raab, M.S.; et al. Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma. N. Engl. J. Med. 2018, 379, 1811–1822. [Google Scholar] [CrossRef]
- Dimopoulos, M.A.; Moreau, P.; Palumbo, A.; Joshua, D.; Pour, L.; Hájek, R.; Facon, T.; Ludwig, H.; Oriol, A.; Goldschmidt, H.; et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): A randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016, 17, 27–38. [Google Scholar] [CrossRef]
- Dimopoulos, M.A.; Oriol, A.; Nahi, H.; San-Miguel, J.; Bahlis, N.J.; Usmani, S.Z.; Rabin, N.; Orlowski, R.Z.; Komarnicki, M.; Suzuki, K.; et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N. Engl. J. Med. 2016, 375, 1319–1331. [Google Scholar] [CrossRef] [Green Version]
- Stewart, A.K.; Rajkumar, S.V.; Dimopoulos, M.A.; Masszi, T.; Špička, I.; Oriol, A.; Hájek, R.; Rosiñol, L.; Siegel, D.S.; Mihaylov, G.G.; et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N. Engl. J. Med. 2015, 372, 142–152. [Google Scholar] [CrossRef]
- Attal, M.; Richardson, P.G.; Rajkumar, S.V.; San-Miguel, J.; Beksac, M.; Spicka, I.; Leleu, X.; Schjesvold, F.; Moreau, P.; Dimopoulos, M.A.; et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): A randomised, multicentre, open-label, phase 3 study. Lancet 2019, 394, 2096–2107. [Google Scholar] [CrossRef]
- Raje, N.; Berdeja, J.; Lin, Y.; Siegel, D.; Jagannath, S.; Madduri, D.; Liedtke, M.; Rosenblatt, J.; Maus, M.V.; Turka, A.; et al. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. N. Engl. J. Med. 2019, 380, 1726–1737. [Google Scholar] [CrossRef]
- Rajkumar, S.V. Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management. Am. J. Hematol. 2016, 91, 719–734. [Google Scholar] [CrossRef] [Green Version]
- Gandhi, U.H.; Cornell, R.F.; Lakshman, A.; Gahvari, Z.J.; McGehee, E.; Jagosky, M.H.; Gupta, R.; Varnado, W.; Fiala, M.A.; Chhabra, S.; et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia 2019, 33, 2266–2275. [Google Scholar] [CrossRef]
- Cicenas, J.; Zalyte, E.; Bairoch, A.; Gaudet, P. Kinases and Cancer. Cancers 2018, 10, 63. [Google Scholar] [CrossRef] [Green Version]
- Hunter, T.; Cooper, J.A. Protein-tyrosine kinases. Annu. Rev. Biochem. 1985, 54, 897–930. [Google Scholar] [CrossRef]
- Chapman, P.B.; Hauschild, A.; Robert, C.; Haanen, J.B.; Ascierto, P.; Larkin, J.; Dummer, R.; Garbe, C.; Testori, A.; Maio, M.; et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 2011, 364, 2507–2516. [Google Scholar] [CrossRef] [Green Version]
- Drilon, A.; Laetsch, T.W.; Kummar, S.; DuBois, S.G.; Lassen, U.N.; Demetri, G.D.; Nathenson, M.; Doebele, R.C.; Farago, A.F.; Pappo, A.S.; et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N. Engl. J. Med. 2018, 378, 731–739. [Google Scholar] [CrossRef]
- Druker, B.J.; Talpaz, M.; Resta, D.J.; Peng, B.; Buchdunger, E.; Ford, J.M.; Lydon, N.B.; Kantarjian, H.; Capdeville, R.; Ohno-Jones, S.; et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 2001, 344, 1031–1037. [Google Scholar] [CrossRef] [Green Version]
- Shaw, A.T.; Ou, S.H.; Bang, Y.J.; Camidge, D.R.; Solomon, B.J.; Salgia, R.; Riely, G.J.; Varella-Garcia, M.; Shapiro, G.I.; Costa, D.B.; et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N. Engl. J. Med. 2014, 371, 1963–1971. [Google Scholar] [CrossRef] [Green Version]
- Camidge, D.R.; Bang, Y.J.; Kwak, E.L.; Iafrate, A.J.; Varella-Garcia, M.; Fox, S.B.; Riely, G.J.; Solomon, B.; Ou, S.H.; Kim, D.W.; et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: Updated results from a phase 1 study. Lancet Oncol. 2012, 13, 1011–1019. [Google Scholar] [CrossRef] [Green Version]
- Rowley, J.D. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973, 243, 290–293. [Google Scholar] [CrossRef]
- Lohr, J.G.; Stojanov, P.; Carter, S.L.; Cruz-Gordillo, P.; Lawrence, M.S.; Auclair, D.; Sougnez, C.; Knoechel, B.; Gould, J.; Saksena, G.; et al. Widespread genetic heterogeneity in multiple myeloma: Implications for targeted therapy. Cancer Cell 2014, 25, 91–101. [Google Scholar] [CrossRef] [Green Version]
- Rasche, L.; Chavan, S.S.; Stephens, O.W.; Patel, P.H.; Tytarenko, R.; Ashby, C.; Bauer, M.; Stein, C.; Deshpande, S.; Wardell, C.; et al. Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing. Nat. Commun. 2017, 8, 268. [Google Scholar] [CrossRef]
- Zhan, F.; Huang, Y.; Colla, S.; Stewart, J.P.; Hanamura, I.; Gupta, S.; Epstein, J.; Yaccoby, S.; Sawyer, J.; Burington, B.; et al. The molecular classification of multiple myeloma. Blood 2006, 108, 2020–2028. [Google Scholar] [CrossRef] [Green Version]
- Bergsagel, P.L.; Kuehl, W.M.; Zhan, F.; Sawyer, J.; Barlogie, B.; Shaughnessy, J., Jr. Cyclin D dysregulation: An early and unifying pathogenic event in multiple myeloma. Blood 2005, 106, 296–303. [Google Scholar] [CrossRef] [Green Version]
- Misund, K.; Keane, N.; Stein, C.K.; Asmann, Y.W.; Day, G.; Welsh, S.; Van Wier, S.A.; Riggs, D.L.; Ahmann, G.; Chesi, M.; et al. MYC dysregulation in the progression of multiple myeloma. Leukemia 2020, 34, 322–326. [Google Scholar] [CrossRef]
- Lakshman, A.; Painuly, U.; Rajkumar, S.V.; Ketterling, R.P.; Kapoor, P.; Greipp, P.T.; Dispenzieri, A.; Gertz, M.A.; Buadi, F.K.; Lacy, M.Q.; et al. Impact of acquired del(17p) in multiple myeloma. Blood Adv. 2019, 3, 1930–1938. [Google Scholar] [CrossRef]
- Walker, B.A.; Mavrommatis, K.; Wardell, C.P.; Ashby, T.C.; Bauer, M.; Davies, F.E.; Rosenthal, A.; Wang, H.; Qu, P.; Hoering, A.; et al. Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma. Blood 2018, 132, 587–597. [Google Scholar] [CrossRef]
- Walker, B.A.; Mavrommatis, K.; Wardell, C.P.; Ashby, T.C.; Bauer, M.; Davies, F.; Rosenthal, A.; Wang, H.; Qu, P.; Hoering, A.; et al. A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis. Leukemia 2019, 33, 159–170. [Google Scholar] [CrossRef]
- Chapman, M.A.; Lawrence, M.S.; Keats, J.J.; Cibulskis, K.; Sougnez, C.; Schinzel, A.C.; Harview, C.L.; Brunet, J.P.; Ahmann, G.J.; Adli, M.; et al. Initial genome sequencing and analysis of multiple myeloma. Nature 2011, 471, 467–472. [Google Scholar] [CrossRef]
- Morgan, G.J.; Walker, B.A.; Davies, F.E. The genetic architecture of multiple myeloma. Nat. Rev. Cancer 2012, 12, 335–348. [Google Scholar] [CrossRef]
- Hideshima, T.; Anderson, K.C. Signaling Pathway Mediating Myeloma Cell Growth and Survival. Cancers 2021, 13, 216. [Google Scholar] [CrossRef]
- Lind, J.; Czernilofsky, F.; Vallet, S.; Podar, K. Emerging protein kinase inhibitors for the treatment of multiple myeloma. Expert Opin. Emerg. Drugs 2019, 24, 133–152. [Google Scholar] [CrossRef] [PubMed]
- Chong, P.S.Y.; Chng, W.J.; de Mel, S. STAT3: A Promising Therapeutic Target in Multiple Myeloma. Cancers 2019, 11, 731. [Google Scholar] [CrossRef] [Green Version]
- Wong, A.H.; Shin, E.M.; Tergaonkar, V.; Chng, W.J. Targeting NF-κB Signaling for Multiple Myeloma. Cancers 2020, 12, 2203. [Google Scholar] [CrossRef] [PubMed]
- Chang, E.H.; Gonda, M.A.; Ellis, R.W.; Scolnick, E.M.; Lowy, D.R. Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses. Proc. Natl. Acad. Sci. USA 1982, 79, 4848–4852. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Degirmenci, U.; Wang, M.; Hu, J. Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy. Cells 2020, 9, 198. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Flaherty, K.T.; Puzanov, I.; Kim, K.B.; Ribas, A.; McArthur, G.A.; Sosman, J.A.; O’Dwyer, P.J.; Lee, R.J.; Grippo, J.F.; Nolop, K.; et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 2010, 363, 809–819. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dietrich, S.; Glimm, H.; Andrulis, M.; von Kalle, C.; Ho, A.D.; Zenz, T. BRAF inhibition in refractory hairy-cell leukemia. N. Engl. J. Med. 2012, 366, 2038–2040. [Google Scholar] [CrossRef]
- Hyman, D.M.; Puzanov, I.; Subbiah, V.; Faris, J.E.; Chau, I.; Blay, J.Y.; Wolf, J.; Raje, N.S.; Diamond, E.L.; Hollebecque, A.; et al. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N. Engl. J. Med. 2015, 373, 726–736. [Google Scholar] [CrossRef]
- Kopetz, S.; Grothey, A.; Yaeger, R.; Van Cutsem, E.; Desai, J.; Yoshino, T.; Wasan, H.; Ciardiello, F.; Loupakis, F.; Hong, Y.S.; et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. N. Engl. J. Med. 2019, 381, 1632–1643. [Google Scholar] [CrossRef] [Green Version]
- Planchard, D.; Besse, B.; Groen, H.J.M.; Souquet, P.J.; Quoix, E.; Baik, C.S.; Barlesi, F.; Kim, T.M.; Mazieres, J.; Novello, S.; et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: An open-label, multicentre phase 2 trial. Lancet Oncol. 2016, 17, 984–993. [Google Scholar] [CrossRef] [Green Version]
- Chng, W.J.; Gonzalez-Paz, N.; Price-Troska, T.; Jacobus, S.; Rajkumar, S.V.; Oken, M.M.; Kyle, R.A.; Henderson, K.J.; Van Wier, S.; Greipp, P.; et al. Clinical and biological significance of RAS mutations in multiple myeloma. Leukemia 2008, 22, 2280–2284. [Google Scholar] [CrossRef] [Green Version]
- Xu, J.; Pfarr, N.; Endris, V.; Mai, E.K.; Md Hanafiah, N.H.; Lehners, N.; Penzel, R.; Weichert, W.; Ho, A.D.; Schirmacher, P.; et al. Molecular signaling in multiple myeloma: Association of RAS/RAF mutations and MEK/ERK pathway activation. Oncogenesis 2017, 6, e337. [Google Scholar] [CrossRef] [Green Version]
- Kortüm, K.M.; Mai, E.K.; Hanafiah, N.H.; Shi, C.X.; Zhu, Y.X.; Bruins, L.; Barrio, S.; Jedlowski, P.; Merz, M.; Xu, J.; et al. Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes. Blood 2016, 128, 1226–1233. [Google Scholar] [CrossRef] [Green Version]
- Mulligan, G.; Lichter, D.I.; Di Bacco, A.; Blakemore, S.J.; Berger, A.; Koenig, E.; Bernard, H.; Trepicchio, W.; Li, B.; Neuwirth, R.; et al. Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy. Blood 2014, 123, 632–639. [Google Scholar] [CrossRef] [Green Version]
- Liu, P.; Leong, T.; Quam, L.; Billadeau, D.; Kay, N.E.; Greipp, P.; Kyle, R.A.; Oken, M.M.; Van Ness, B. Activating mutations of N- and K-ras in multiple myeloma show different clinical associations: Analysis of the Eastern Cooperative Oncology Group Phase III Trial. Blood 1996, 88, 2699–2706. [Google Scholar] [CrossRef]
- Smith, D.; Armenteros, E.; Percy, L.; Kumar, M.; Lach, A.; Herledan, G.; Stubbs, M.; Downward, J.; Yong, K. RAS mutation status and bortezomib therapy for relapsed multiple myeloma. Br. J. Haematol. 2015, 169, 905–908. [Google Scholar] [CrossRef]
- Walker, B.A.; Boyle, E.M.; Wardell, C.P.; Murison, A.; Begum, D.B.; Dahir, N.M.; Proszek, P.Z.; Johnson, D.C.; Kaiser, M.F.; Melchor, L.; et al. Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma. J. Clin. Oncol. 2015, 33, 3911–3920. [Google Scholar] [CrossRef]
- Downward, J. Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer 2003, 3, 11–22. [Google Scholar] [CrossRef]
- Hong, D.S.; Fakih, M.G.; Strickler, J.H.; Desai, J.; Durm, G.A.; Shapiro, G.I.; Falchook, G.S.; Price, T.J.; Sacher, A.; Denlinger, C.S.; et al. KRAS(G12C) Inhibition with Sotorasib in Advanced Solid Tumors. N. Engl. J. Med. 2020, 383, 1207–1217. [Google Scholar] [CrossRef]
- Alsina, M.; Fonseca, R.; Wilson, E.F.; Belle, A.N.; Gerbino, E.; Price-Troska, T.; Overton, R.M.; Ahmann, G.; Bruzek, L.M.; Adjei, A.A.; et al. Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma. Blood 2004, 103, 3271–3277. [Google Scholar] [CrossRef] [Green Version]
- Lito, P.; Pratilas, C.A.; Joseph, E.W.; Tadi, M.; Halilovic, E.; Zubrowski, M.; Huang, A.; Wong, W.L.; Callahan, M.K.; Merghoub, T.; et al. Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 2012, 22, 668–682. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Heidorn, S.J.; Milagre, C.; Whittaker, S.; Nourry, A.; Niculescu-Duvas, I.; Dhomen, N.; Hussain, J.; Reis-Filho, J.S.; Springer, C.J.; Pritchard, C.; et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 2010, 140, 209–221. [Google Scholar] [CrossRef] [PubMed]
- Kamata, T.; Hussain, J.; Giblett, S.; Hayward, R.; Marais, R.; Pritchard, C. BRAF inactivation drives aneuploidy by deregulating CRAF. Cancer Res. 2010, 70, 8475–8486. [Google Scholar] [CrossRef] [Green Version]
- Garnett, M.J.; Rana, S.; Paterson, H.; Barford, D.; Marais, R. Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol. Cell 2005, 20, 963–969. [Google Scholar] [CrossRef] [PubMed]
- Hatzivassiliou, G.; Song, K.; Yen, I.; Brandhuber, B.J.; Anderson, D.J.; Alvarado, R.; Ludlam, M.J.; Stokoe, D.; Gloor, S.L.; Vigers, G.; et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010, 464, 431–435. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Heuck, C.J.; Jethava, Y.; Khan, R.; van Rhee, F.; Zangari, M.; Chavan, S.; Robbins, K.; Miller, S.E.; Matin, A.; Mohan, M.; et al. Inhibiting MEK in MAPK pathway-activated myeloma. Leukemia 2016, 30, 976–980. [Google Scholar] [CrossRef]
- Emery, C.M.; Monaco, K.A.; Wang, P.; Balak, M.; Freeman, A.; Meltzer, J.; Delach, S.M.; Rakiec, D.; Ruddy, D.A.; Korn, J.M.; et al. BRAF-inhibitor Associated MEK Mutations Increase RAF-Dependent and -Independent Enzymatic Activity. Mol. Cancer Res. 2017, 15, 1431–1444. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wagle, N.; Emery, C.; Berger, M.F.; Davis, M.J.; Sawyer, A.; Pochanard, P.; Kehoe, S.M.; Johannessen, C.M.; Macconaill, L.E.; Hahn, W.C.; et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J. Clin. Oncol. 2011, 29, 3085–3096. [Google Scholar] [CrossRef] [Green Version]
- Nazarian, R.; Shi, H.; Wang, Q.; Kong, X.; Koya, R.C.; Lee, H.; Chen, Z.; Lee, M.K.; Attar, N.; Sazegar, H.; et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010, 468, 973–977. [Google Scholar] [CrossRef] [Green Version]
- Turke, A.B.; Song, Y.; Costa, C.; Cook, R.; Arteaga, C.L.; Asara, J.M.; Engelman, J.A. MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors. Cancer Res. 2012, 72, 3228–3237. [Google Scholar] [CrossRef] [Green Version]
- Long, G.V.; Stroyakovskiy, D.; Gogas, H.; Levchenko, E.; de Braud, F.; Larkin, J.; Garbe, C.; Jouary, T.; Hauschild, A.; Grob, J.J.; et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N. Engl. J. Med. 2014, 371, 1877–1888. [Google Scholar] [CrossRef] [Green Version]
- Andrulis, M.; Lehners, N.; Capper, D.; Penzel, R.; Heining, C.; Huellein, J.; Zenz, T.; von Deimling, A.; Schirmacher, P.; Ho, A.D.; et al. Targeting the BRAF V600E mutation in multiple myeloma. Cancer Discov. 2013, 3, 862–869. [Google Scholar] [CrossRef] [Green Version]
- Mey, U.J.M.; Renner, C.; von Moos, R. Vemurafenib in combination with cobimetinib in relapsed and refractory extramedullary multiple myeloma harboring the BRAF V600E mutation. Hematol. Oncol. 2017, 35, 890–893. [Google Scholar] [CrossRef]
- Sharman, J.P.; Chmielecki, J.; Morosini, D.; Palmer, G.A.; Ross, J.S.; Stephens, P.J.; Stafl, J.; Miller, V.A.; Ali, S.M. Vemurafenib response in 2 patients with posttransplant refractory BRAF V600E-mutated multiple myeloma. Clin. Lymphoma Myeloma Leuk. 2014, 14, e161–e163. [Google Scholar] [CrossRef]
- Salama, A.K.S.; Li, S.; Macrae, E.R.; Park, J.I.; Mitchell, E.P.; Zwiebel, J.A.; Chen, H.X.; Gray, R.J.; McShane, L.M.; Rubinstein, L.V.; et al. Dabrafenib and Trametinib in Patients with Tumors With BRAF(V600E) Mutations: Results of the NCI-MATCH Trial Subprotocol H. J. Clin. Oncol. 2020, 38, 3895–3904. [Google Scholar] [CrossRef]
- Guo, C.; Chénard-Poirier, M.; Roda, D.; de Miguel, M.; Harris, S.J.; Candilejo, I.M.; Sriskandarajah, P.; Xu, W.; Scaranti, M.; Constantinidou, A.; et al. Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: A single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study. Lancet Oncol. 2020, 21, 1478–1488. [Google Scholar] [CrossRef]
- Raab, M.S.; Giesen, N.; Scheid, C.; Besemer, B.; Miah, K.; Benner, A.; Metzler, I.; Khandanpour, C.; Seidel-Glaetzer, A.; Trautmann-Grill, K.; et al. Safety and Preliminary Efficacy Results from a Phase II Study Evaluating Combined BRAF and MEK Inhibition in Relapsed/Refractory Multiple Myeloma (rrMM) Patients with Activating BRAF V600E Mutations: The GMMG-Birma Trial. Blood 2020, 136, 44–45. [Google Scholar] [CrossRef]
- Schjesvold, F.; Ribrag, V.; Rodriguez-Otero, P.; Robak, P.J.; Hansson, M.; Hajek, R.; Amor, A.A.; Martinez-López, J.; Onishi, M.; Gallo, J.D.; et al. Safety and Preliminary Efficacy Results from a Phase Ib/II Study of Cobimetinib As a Single Agent and in Combination with Venetoclax with or without Atezolizumab in Patients with Relapsed/Refractory Multiple Myeloma. Blood 2020, 136, 45–46. [Google Scholar] [CrossRef]
- Keane, N.A.; Glavey, S.V.; Krawczyk, J.; O’Dwyer, M. AKT as a therapeutic target in multiple myeloma. Expert Opin. Ther. Targets 2014, 18, 897–915. [Google Scholar] [CrossRef]
- Manning, B.D.; Toker, A. AKT/PKB Signaling: Navigating the Network. Cell 2017, 169, 381–405. [Google Scholar] [CrossRef] [Green Version]
- Hsu, J.; Shi, Y.; Krajewski, S.; Renner, S.; Fisher, M.; Reed, J.C.; Franke, T.F.; Lichtenstein, A. The AKT kinase is activated in multiple myeloma tumor cells. Blood 2001, 98, 2853–2855. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ismail, S.I.; Mahmoud, I.S.; Msallam, M.M.; Sughayer, M.A. Hotspot mutations of PIK3CA and AKT1 genes are absent in multiple myeloma. Leuk. Res. 2010, 34, 824–826. [Google Scholar] [CrossRef] [PubMed]
- Podar, K.; Tai, Y.T.; Cole, C.E.; Hideshima, T.; Sattler, M.; Hamblin, A.; Mitsiades, N.; Schlossman, R.L.; Davies, F.E.; Morgan, G.J.; et al. Essential role of caveolae in interleukin-6- and insulin-like growth factor I-triggered Akt-1-mediated survival of multiple myeloma cells. J. Biol. Chem. 2003, 278, 5794–5801. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hu, L.; Shi, Y.; Hsu, J.H.; Gera, J.; Van Ness, B.; Lichtenstein, A. Downstream effectors of oncogenic ras in multiple myeloma cells. Blood 2003, 101, 3126–3135. [Google Scholar] [CrossRef] [Green Version]
- Mitsiades, C.S.; Mitsiades, N.; Poulaki, V.; Schlossman, R.; Akiyama, M.; Chauhan, D.; Hideshima, T.; Treon, S.P.; Munshi, N.C.; Richardson, P.G.; et al. Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: Therapeutic implications. Oncogene 2002, 21, 5673–5683. [Google Scholar] [CrossRef] [Green Version]
- Hideshima, T.; Nakamura, N.; Chauhan, D.; Anderson, K.C. Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene 2001, 20, 5991–6000. [Google Scholar] [CrossRef] [Green Version]
- Ramakrishnan, V.; Kimlinger, T.; Haug, J.; Painuly, U.; Wellik, L.; Halling, T.; Rajkumar, S.V.; Kumar, S. Anti-myeloma activity of Akt inhibition is linked to the activation status of PI3K/Akt and MEK/ERK pathway. PLoS ONE 2012, 7, e50005. [Google Scholar] [CrossRef] [Green Version]
- Richardson, P.; Lonial, S.; Jakubowiak, A.; Krishnan, A.; Wolf, J.; Densmore, J.; Singhal, S.; Ghobrial, I.; Stephenson, J.; Mehta, J.; et al. Multi-Center Phase II Study of Perifosine (KRX-0401) Alone and in Combination with Dexamethasone (dex) for Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Promising Activity as Combination Therapy with Manageable Toxicity. Blood 2007, 110, 1164. [Google Scholar] [CrossRef]
- Jakubowiak, A.J.; Richardson, P.G.; Zimmerman, T.; Alsina, M.; Kaufman, J.L.; Kandarpa, M.; Kraftson, S.; Ross, C.W.; Harvey, C.; Hideshima, T.; et al. Perifosine plus lenalidomide and dexamethasone in relapsed and relapsed/refractory multiple myeloma: A Phase I Multiple Myeloma Research Consortium study. Br. J. Haematol. 2012, 158, 472–480. [Google Scholar] [CrossRef] [Green Version]
- Richardson, P.G.; Wolf, J.; Jakubowiak, A.; Zonder, J.; Lonial, S.; Irwin, D.; Densmore, J.; Krishnan, A.; Raje, N.; Bar, M.; et al. Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: Results of a multicenter phase I/II trial. J. Clin. Oncol. 2011, 29, 4243–4249. [Google Scholar] [CrossRef]
- Richardson, P.G.; Nagler, A.; Ben-Yehuda, D.; Badros, A.; Hari, P.N.; Hajek, R.; Spicka, I.; Kaya, H.; LeBlanc, R.; Yoon, S.-S.; et al. Randomized, placebo-controlled, phase 3 study of perifosine combined with bortezomib and dexamethasone in patients with relapsed, refractory multiple myeloma previously treated with bortezomib. eJHaem 2020, 1, 94–102. [Google Scholar] [CrossRef]
- Spencer, A.; Yoon, S.S.; Harrison, S.J.; Morris, S.R.; Smith, D.A.; Brigandi, R.A.; Gauvin, J.; Kumar, R.; Opalinska, J.B.; Chen, C. The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. Blood 2014, 124, 2190–2195. [Google Scholar] [CrossRef] [Green Version]
- Lehners, N.; Xu, J.; Hielscher, T.; Rasche, L.; Ellert, E.; Stenzinger, A.; Schirmacher, P.; Müller-Tidow, C.; Goldschmidt, H.; Andrulis, M.; et al. Profiling of Oncogenic Signaling in Multiple Myeloma—Association with Biology, Disease Progression and Prognosis. Blood 2018, 132, 3206. [Google Scholar] [CrossRef]
- Voorhees, P.M.; Spencer, A.; Sutherland, H.J.; O’Dwyer, M.E.; Huang, S.-Y.; Stewart, K.; Chari, A.; Rosenzwieg, M.; Nooka, A.K.; Rosenbaum, C.A.; et al. Novel AKT Inhibitor Afuresertib in Combination with Bortezomib and Dexamethasone Demonstrates Favorable Safety Profile and Significant Clinical Activity in Patients with Relapsed/Refractory Multiple Myeloma. Blood 2013, 122, 283. [Google Scholar] [CrossRef]
- Steinbrunn, T.; Stühmer, T.; Gattenlöhner, S.; Rosenwald, A.; Mottok, A.; Unzicker, C.; Einsele, H.; Chatterjee, M.; Bargou, R.C. Mutated RAS and constitutively activated Akt delineate distinct oncogenic pathways, which independently contribute to multiple myeloma cell survival. Blood 2011, 117, 1998–2004. [Google Scholar] [CrossRef] [Green Version]
- Lentzsch, S.; Chatterjee, M.; Gries, M.; Bommert, K.; Gollasch, H.; Dörken, B.; Bargou, R.C. PI3-K/AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells. Leukemia 2004, 18, 1883–1890. [Google Scholar] [CrossRef] [Green Version]
- Rowley, M.; Liu, P.; Van Ness, B. Heterogeneity in therapeutic response of genetically altered myeloma cell lines to interleukin 6, dexamethasone, doxorubicin, and melphalan. Blood 2000, 96, 3175–3180. [Google Scholar] [CrossRef]
- Tolcher, A.W.; Patnaik, A.; Papadopoulos, K.P.; Rasco, D.W.; Becerra, C.R.; Allred, A.J.; Orford, K.; Aktan, G.; Ferron-Brady, G.; Ibrahim, N.; et al. Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Cancer Chemother. Pharmacol. 2015, 75, 183–189. [Google Scholar] [CrossRef]
- Frost, P.; Moatamed, F.; Hoang, B.; Shi, Y.; Gera, J.; Yan, H.; Frost, P.; Gibbons, J.; Lichtenstein, A. In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model. Blood 2004, 104, 4181–4187. [Google Scholar] [CrossRef] [Green Version]
- Günther, A.; Baumann, P.; Burger, R.; Kellner, C.; Klapper, W.; Schmidmaier, R.; Gramatzki, M. Activity of everolimus (RAD001) in relapsed and/or refractory multiple myeloma: A phase I study. Haematologica 2015, 100, 541–547. [Google Scholar] [CrossRef] [Green Version]
- Farag, S.S.; Zhang, S.; Jansak, B.S.; Wang, X.; Kraut, E.; Chan, K.; Dancey, J.E.; Grever, M.R. Phase II trial of temsirolimus in patients with relapsed or refractory multiple myeloma. Leuk. Res. 2009, 33, 1475–1480. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ghobrial, I.M.; Weller, E.; Vij, R.; Munshi, N.C.; Banwait, R.; Bagshaw, M.; Schlossman, R.; Leduc, R.; Chuma, S.; Kunsman, J.; et al. Weekly bortezomib in combination with temsirolimus in relapsed or relapsed and refractory multiple myeloma: A multicentre, phase 1/2, open-label, dose-escalation study. Lancet Oncol. 2011, 12, 263–272. [Google Scholar] [CrossRef]
- Yee, A.J.; Hari, P.; Marcheselli, R.; Mahindra, A.K.; Cirstea, D.D.; Scullen, T.A.; Burke, J.N.; Rodig, S.J.; Hideshima, T.; Laubach, J.P.; et al. Outcomes in patients with relapsed or refractory multiple myeloma in a phase I study of everolimus in combination with lenalidomide. Br. J. Haematol. 2014, 166, 401–409. [Google Scholar] [CrossRef] [PubMed]
- Ghobrial, I.M.; Siegel, D.S.; Vij, R.; Berdeja, J.G.; Richardson, P.G.; Neuwirth, R.; Patel, C.G.; Zohren, F.; Wolf, J.L. TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström’s macroglobulinemia. Am. J. Hematol. 2016, 91, 400–405. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zöllinger, A.; Stühmer, T.; Chatterjee, M.; Gattenlöhner, S.; Haralambieva, E.; Müller-Hermelink, H.K.; Andrulis, M.; Greiner, A.; Wesemeier, C.; Rath, J.C.; et al. Combined functional and molecular analysis of tumor cell signaling defines 2 distinct myeloma subgroups: Akt-dependent and Akt-independent multiple myeloma. Blood 2008, 112, 3403–3411. [Google Scholar] [CrossRef] [PubMed]
- Cuypers, H.T.; Selten, G.; Quint, W.; Zijlstra, M.; Maandag, E.R.; Boelens, W.; van Wezenbeek, P.; Melief, C.; Berns, A. Murine leukemia virus-induced T-cell lymphomagenesis: Integration of proviruses in a distinct chromosomal region. Cell 1984, 37, 141–150. [Google Scholar] [CrossRef]
- van Lohuizen, M.; Verbeek, S.; Krimpenfort, P.; Domen, J.; Saris, C.; Radaszkiewicz, T.; Berns, A. Predisposition to lymphomagenesis in pim-1 transgenic mice: Cooperation with c-myc and N-myc in murine leukemia virus-induced tumors. Cell 1989, 56, 673–682. [Google Scholar] [CrossRef]
- Amson, R.; Sigaux, F.; Przedborski, S.; Flandrin, G.; Givol, D.; Telerman, A. The human protooncogene product p33pim is expressed during fetal hematopoiesis and in diverse leukemias. Proc. Natl. Acad. Sci. USA 1989, 86, 8857–8861. [Google Scholar] [CrossRef] [Green Version]
- Lu, J.; Zavorotinskaya, T.; Dai, Y.; Niu, X.H.; Castillo, J.; Sim, J.; Yu, J.; Wang, Y.; Langowski, J.L.; Holash, J.; et al. Pim2 is required for maintaining multiple myeloma cell growth through modulating TSC2 phosphorylation. Blood 2013, 122, 1610–1620. [Google Scholar] [CrossRef]
- Asano, J.; Nakano, A.; Oda, A.; Amou, H.; Hiasa, M.; Takeuchi, K.; Miki, H.; Nakamura, S.; Harada, T.; Fujii, S.; et al. The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells. Leukemia 2011, 25, 1182–1188. [Google Scholar] [CrossRef] [Green Version]
- Mochizuki, T.; Kitanaka, C.; Noguchi, K.; Muramatsu, T.; Asai, A.; Kuchino, Y. Physical and functional interactions between Pim-1 kinase and Cdc25A phosphatase. Implications for the Pim-1-mediated activation of the c-Myc signaling pathway. J. Biol. Chem. 1999, 274, 18659–18666. [Google Scholar] [CrossRef] [Green Version]
- Bachmann, M.; Hennemann, H.; Xing, P.X.; Hoffmann, I.; Möröy, T. The oncogenic serine/threonine kinase Pim-1 phosphorylates and inhibits the activity of Cdc25C-associated kinase 1 (C-TAK1): A novel role for Pim-1 at the G2/M cell cycle checkpoint. J. Biol. Chem. 2004, 279, 48319–48328. [Google Scholar] [CrossRef] [Green Version]
- Hiasa, M.; Teramachi, J.; Oda, A.; Amachi, R.; Harada, T.; Nakamura, S.; Miki, H.; Fujii, S.; Kagawa, K.; Watanabe, K.; et al. Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma. Leukemia 2015, 29, 207–217. [Google Scholar] [CrossRef]
- Chen, J.; Kobayashi, M.; Darmanin, S.; Qiao, Y.; Gully, C.; Zhao, R.; Yeung, S.C.; Lee, M.H. Pim-1 plays a pivotal role in hypoxia-induced chemoresistance. Oncogene 2009, 28, 2581–2592. [Google Scholar] [CrossRef] [Green Version]
- Raab, M.S.; Thomas, S.K.; Ocio, E.M.; Guenther, A.; Goh, Y.T.; Talpaz, M.; Hohmann, N.; Zhao, S.; Xiang, F.; Simon, C.; et al. The first-in-human study of the pan-PIM kinase inhibitor PIM447 in patients with relapsed and/or refractory multiple myeloma. Leukemia 2019, 33, 2924–2933. [Google Scholar] [CrossRef]
- Keane, N.A.; Reidy, M.; Natoni, A.; Raab, M.S.; O’Dwyer, M. Targeting the Pim kinases in multiple myeloma. Blood Cancer J. 2015, 5, e325. [Google Scholar] [CrossRef] [Green Version]
- Paíno, T.; González-Méndez, L.; San-Segundo, L.; Corchete, L.A.; Hernández-García, S.; Díaz-Tejedor, A.; Algarín, E.M.; Mogollón, P.; Martín-Sánchez, M.; Gutiérrez, N.C.; et al. Protein Translation Inhibition is Involved in the Activity of the Pan-PIM Kinase Inhibitor PIM447 in Combination with Pomalidomide-Dexamethasone in Multiple Myeloma. Cancers 2020, 12, 743. [Google Scholar] [CrossRef]
- Li, S.; Vallet, S.; Sacco, A.; Roccaro, A.; Lentzsch, S.; Podar, K. Targeting transcription factors in multiple myeloma: Evolving therapeutic strategies. Expert Opin. Investig. Drugs 2019, 28, 445–462. [Google Scholar] [CrossRef]
- Jovanović, K.K.; Roche-Lestienne, C.; Ghobrial, I.M.; Facon, T.; Quesnel, B.; Manier, S. Targeting MYC in multiple myeloma. Leukemia 2018, 32, 1295–1306. [Google Scholar] [CrossRef]
- Vennstrom, B.; Sheiness, D.; Zabielski, J.; Bishop, J.M. Isolation and characterization of c-myc, a cellular homolog of the oncogene (v-myc) of avian myelocytomatosis virus strain 29. J. Virol. 1982, 42, 773–779. [Google Scholar] [CrossRef] [Green Version]
- Dalla-Favera, R.; Bregni, M.; Erikson, J.; Patterson, D.; Gallo, R.C.; Croce, C.M. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc. Natl. Acad. Sci. USA 1982, 79, 7824–7827. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pourdehnad, M.; Truitt, M.L.; Siddiqi, I.N.; Ducker, G.S.; Shokat, K.M.; Ruggero, D. Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc. Natl. Acad. Sci. USA 2013, 110, 11988–11993. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chng, W.J.; Huang, G.F.; Chung, T.H.; Ng, S.B.; Gonzalez-Paz, N.; Troska-Price, T.; Mulligan, G.; Chesi, M.; Bergsagel, P.L.; Fonseca, R. Clinical and biological implications of MYC activation: A common difference between MGUS and newly diagnosed multiple myeloma. Leukemia 2011, 25, 1026–1035. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sears, R.; Leone, G.; DeGregori, J.; Nevins, J.R. Ras enhances Myc protein stability. Mol. Cell 1999, 3, 169–179. [Google Scholar] [CrossRef]
- Sears, R.; Nuckolls, F.; Haura, E.; Taya, Y.; Tamai, K.; Nevins, J.R. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev. 2000, 14, 2501–2514. [Google Scholar] [CrossRef] [Green Version]
- Chesi, M.; Robbiani, D.F.; Sebag, M.; Chng, W.J.; Affer, M.; Tiedemann, R.; Valdez, R.; Palmer, S.E.; Haas, S.S.; Stewart, A.K.; et al. AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies. Cancer Cell 2008, 13, 167–180. [Google Scholar] [CrossRef] [Green Version]
- Delmore, J.E.; Issa, G.C.; Lemieux, M.E.; Rahl, P.B.; Shi, J.; Jacobs, H.M.; Kastritis, E.; Gilpatrick, T.; Paranal, R.M.; Qi, J.; et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011, 146, 904–917. [Google Scholar] [CrossRef] [Green Version]
- Amorim, S.; Stathis, A.; Gleeson, M.; Iyengar, S.; Magarotto, V.; Leleu, X.; Morschhauser, F.; Karlin, L.; Broussais, F.; Rezai, K.; et al. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: A dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol. 2016, 3, e196–e204. [Google Scholar] [CrossRef]
- Ramasamy, K.; Nooka, A.; Quach, H.; Htut, M.; Popat, R.; Liedtke, M.; Tuchman, S.A.; Laubach, J.P.; Gasparetto, C.; Chanan-Khan, A.A.; et al. Open Label, Multicenter, Dose-Escalation/ Expansion Phase Ib Study to Evaluate Safety and Activity of BET Inhibitor RO6870810 (RO), Given As Monotherapy to Patients (pts) with Advanced Multiple Myeloma. Blood 2020, 136, 12–14. [Google Scholar] [CrossRef]
- Siu, K.T.; Ramachandran, J.; Yee, A.J.; Eda, H.; Santo, L.; Panaroni, C.; Mertz, J.A.; Sims Iii, R.J.; Cooper, M.R.; Raje, N. Preclinical activity of CPI-0610, a novel small-molecule bromodomain and extra-terminal protein inhibitor in the therapy of multiple myeloma. Leukemia 2017, 31, 1760–1769. [Google Scholar] [CrossRef]
- Fong, C.Y.; Gilan, O.; Lam, E.Y.; Rubin, A.F.; Ftouni, S.; Tyler, D.; Stanley, K.; Sinha, D.; Yeh, P.; Morison, J.; et al. BET inhibitor resistance emerges from leukaemia stem cells. Nature 2015, 525, 538–542. [Google Scholar] [CrossRef]
- Ma, Y.; Wang, L.; Neitzel, L.R.; Loganathan, S.N.; Tang, N.; Qin, L.; Crispi, E.E.; Guo, Y.; Knapp, S.; Beauchamp, R.D.; et al. The MAPK Pathway Regulates Intrinsic Resistance to BET Inhibitors in Colorectal Cancer. Clin. Cancer Res. 2017, 23, 2027–2037. [Google Scholar] [CrossRef] [Green Version]
- Wyce, A.; Matteo, J.J.; Foley, S.W.; Felitsky, D.J.; Rajapurkar, S.R.; Zhang, X.P.; Musso, M.C.; Korenchuk, S.; Karpinich, N.O.; Keenan, K.M.; et al. MEK inhibitors overcome resistance to BET inhibition across a number of solid and hematologic cancers. Oncogenesis 2018, 7, 35. [Google Scholar] [CrossRef] [Green Version]
- Wu, T.; Wang, G.; Chen, W.; Zhu, Z.; Liu, Y.; Huang, Z.; Huang, Y.; Du, P.; Yang, Y.; Liu, C.Y.; et al. Co-inhibition of BET proteins and NF-κB as a potential therapy for colorectal cancer through synergistic inhibiting MYC and FOXM1 expressions. Cell Death Dis. 2018, 9, 315. [Google Scholar] [CrossRef]
- Zhang, H.P.; Li, G.Q.; Zhang, Y.; Guo, W.Z.; Zhang, J.K.; Li, J.; Lv, J.F.; Zhang, S.J. Upregulation of Mcl-1 inhibits JQ1-triggered anticancer activity in hepatocellular carcinoma cells. Biochem. Biophys. Res. Commun. 2018, 495, 2456–2461. [Google Scholar] [CrossRef]
- Esteve-Arenys, A.; Valero, J.G.; Chamorro-Jorganes, A.; Gonzalez, D.; Rodriguez, V.; Dlouhy, I.; Salaverria, I.; Campo, E.; Colomer, D.; Martinez, A.; et al. The BET bromodomain inhibitor CPI203 overcomes resistance to ABT-199 (venetoclax) by downregulation of BFL-1/A1 in in vitro and in vivo models of MYC+/BCL2+ double hit lymphoma. Oncogene 2018, 37, 1830–1844. [Google Scholar] [CrossRef]
- Rathert, P.; Roth, M.; Neumann, T.; Muerdter, F.; Roe, J.S.; Muhar, M.; Deswal, S.; Cerny-Reiterer, S.; Peter, B.; Jude, J.; et al. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition. Nature 2015, 525, 543–547. [Google Scholar] [CrossRef]
- Tolcher, A.W.; Papadopoulos, K.P.; Patnaik, A.; Rasco, D.W.; Martinez, D.; Wood, D.L.; Fielman, B.; Sharma, M.; Janisch, L.A.; Brown, B.D.; et al. Safety and activity of DCR-MYC, a first-in-class Dicer-substrate small interfering RNA (DsiRNA) targeting MYC, in a phase I study in patients with advanced solid tumors. J. Clin. Oncol. 2015, 33, 11006. [Google Scholar] [CrossRef]
- Holien, T.; Våtsveen, T.K.; Hella, H.; Waage, A.; Sundan, A. Addiction to c-MYC in multiple myeloma. Blood 2012, 120, 2450–2453. [Google Scholar] [CrossRef] [Green Version]
- Wang, H.; Teriete, P.; Hu, A.; Raveendra-Panickar, D.; Pendelton, K.; Lazo, J.S.; Eiseman, J.; Holien, T.; Misund, K.; Oliynyk, G.; et al. Direct inhibition of c-Myc-Max heterodimers by celastrol and celastrol-inspired triterpenoids. Oncotarget 2015, 6, 32380–32395. [Google Scholar] [CrossRef] [Green Version]
- Manier, S.; Huynh, D.; Shen, Y.J.; Zhou, J.; Yusufzai, T.; Salem, K.Z.; Ebright, R.Y.; Shi, J.; Park, J.; Glavey, S.V.; et al. Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma. Sci. Transl. Med. 2017, 9. [Google Scholar] [CrossRef] [Green Version]
- Deng, C.; Lipstein, M.R.; Scotto, L.; Jirau Serrano, X.O.; Mangone, M.A.; Li, S.; Vendome, J.; Hao, Y.; Xu, X.; Deng, S.X.; et al. Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kδ and CK1ε in hematological malignancies. Blood 2017, 129, 88–99. [Google Scholar] [CrossRef]
- Zhang, X.; Lee, H.C.; Shirazi, F.; Baladandayuthapani, V.; Lin, H.; Kuiatse, I.; Wang, H.; Jones, R.J.; Berkova, Z.; Singh, R.K.; et al. Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma. Leukemia 2018, 32, 2224–2239. [Google Scholar] [CrossRef]
- Malkin, D.; Li, F.P.; Strong, L.C.; Fraumeni, J.F., Jr.; Nelson, C.E.; Kim, D.H.; Kassel, J.; Gryka, M.A.; Bischoff, F.Z.; Tainsky, M.A.; et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990, 250, 1233–1238. [Google Scholar] [CrossRef]
- Kirsch, D.G.; Kastan, M.B. Tumor-suppressor p53: Implications for tumor development and prognosis. J. Clin. Oncol. 1998, 16, 3158–3168. [Google Scholar] [CrossRef]
- Levine, A.J. p53, the cellular gatekeeper for growth and division. Cell 1997, 88, 323–331. [Google Scholar] [CrossRef] [Green Version]
- Weinhold, N.; Ashby, C.; Rasche, L.; Chavan, S.S.; Stein, C.; Stephens, O.W.; Tytarenko, R.; Bauer, M.A.; Meissner, T.; Deshpande, S.; et al. Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma. Blood 2016, 128, 1735–1744. [Google Scholar] [CrossRef] [PubMed]
- Vassilev, L.T.; Vu, B.T.; Graves, B.; Carvajal, D.; Podlaski, F.; Filipovic, Z.; Kong, N.; Kammlott, U.; Lukacs, C.; Klein, C.; et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004, 303, 844–848. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stühmer, T.; Chatterjee, M.; Hildebrandt, M.; Herrmann, P.; Gollasch, H.; Gerecke, C.; Theurich, S.; Cigliano, L.; Manz, R.A.; Daniel, P.T.; et al. Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma. Blood 2005, 106, 3609–3617. [Google Scholar] [CrossRef] [PubMed]
- Saha, M.N.; Jiang, H.; Jayakar, J.; Reece, D.; Branch, D.R.; Chang, H. MDM2 antagonist nutlin plus proteasome inhibitor velcade combination displays a synergistic anti-myeloma activity. Cancer Biol. Ther. 2010, 9, 936–944. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Saha, M.N.; Jiang, H.; Chang, H. Molecular mechanisms of nutlin-induced apoptosis in multiple myeloma: Evidence for p53-transcription-dependent and -independent pathways. Cancer Biol. Ther. 2010, 10, 567–578. [Google Scholar] [CrossRef] [Green Version]
- Surget, S.; Descamps, G.; Brosseau, C.; Normant, V.; Maïga, S.; Gomez-Bougie, P.; Gouy-Colin, N.; Godon, C.; Béné, M.C.; Moreau, P.; et al. RITA (Reactivating p53 and Inducing Tumor Apoptosis) is efficient against TP53abnormal myeloma cells independently of the p53 pathway. BMC Cancer 2014, 14, 437. [Google Scholar] [CrossRef] [Green Version]
- Jones, R.J.; Bjorklund, C.C.; Baladandayuthapani, V.; Kuhn, D.J.; Orlowski, R.Z. Drug resistance to inhibitors of the human double minute-2 E3 ligase is mediated by point mutations of p53, but can be overcome with the p53 targeting agent RITA. Mol. Cancer Ther. 2012, 11, 2243–2253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Issaeva, N.; Bozko, P.; Enge, M.; Protopopova, M.; Verhoef, L.G.; Masucci, M.; Pramanik, A.; Selivanova, G. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat. Med. 2004, 10, 1321–1328. [Google Scholar] [CrossRef]
- Lambert, J.M.; Gorzov, P.; Veprintsev, D.B.; Söderqvist, M.; Segerbäck, D.; Bergman, J.; Fersht, A.R.; Hainaut, P.; Wiman, K.G.; Bykov, V.J. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell 2009, 15, 376–388. [Google Scholar] [CrossRef] [Green Version]
- Saha, M.N.; Jiang, H.; Yang, Y.; Reece, D.; Chang, H. PRIMA-1Met/APR-246 displays high antitumor activity in multiple myeloma by induction of p73 and Noxa. Mol. Cancer Ther. 2013, 12, 2331–2341. [Google Scholar] [CrossRef] [Green Version]
- Tessoulin, B.; Descamps, G.; Moreau, P.; Maïga, S.; Lodé, L.; Godon, C.; Marionneau-Lambot, S.; Oullier, T.; Le Gouill, S.; Amiot, M.; et al. PRIMA-1Met induces myeloma cell death independent of p53 by impairing the GSH/ROS balance. Blood 2014, 124, 1626–1636. [Google Scholar] [CrossRef] [Green Version]
- Teoh, P.J.; Bi, C.; Sintosebastian, C.; Tay, L.S.; Fonseca, R.; Chng, W.J. PRIMA-1 targets the vulnerability of multiple myeloma of deregulated protein homeostasis through the perturbation of ER stress via p73 demethylation. Oncotarget 2016, 7, 61806–61819. [Google Scholar] [CrossRef] [Green Version]
- Figueroa-Vazquez, V.; Ko, J.; Breunig, C.; Baumann, A.; Giesen, N.; Pálfi, A.; Müller, C.; Lutz, C.; Hechler, T.; Kulke, M.; et al. HDP-101, anti-BCMA antibody-drug conjugate, safely delivers amanitin to induce cell death in proliferating and resting multiple myeloma cells. Mol. Cancer Ther. 2020. [Google Scholar] [CrossRef]
- Strassz, A.; Raab, M.S.; Orlowski, R.Z.; Kulke, M.; Schiedner, G.; Pahl, A. A First in Human Study Planned to Evaluate Hdp-101, an Anti-BCMA Amanitin Antibody-Drug Conjugate with a New Payload and a New Mode of Action, in Multiple Myeloma. Blood 2020, 136, 34. [Google Scholar] [CrossRef]
Study | Drugs | Study Type | Efficacy | Patient Selection |
---|---|---|---|---|
RAS/RAF/MEK/ERK-pathway | ||||
Alsina et al. [50] | Tipifarnib | Phase II | 64% stable disease, 0% ≥ PR | r/r MM |
Heuck et al. [56] | Trametinib | Retrospective cohort | 10% ≥ PR | Mutations in NRAS, KRAS, BRAF, MAPK-activation in GEP |
Hyman D.M. et al. [38] | Vemurafenib | Phase II Basket-trial | No responses in the 5 MM patients | BRAFV600 mutated |
NCI-MATCH [65] | Dabrafenib + Trametinib | Phase II Basket-trial | No response in myeloma patients | BRAF V600E/R/K/D mutated |
BIRMA-Study [67] | Encorafenib + Binimetinib | Phase II | ORR (≥PR) 82% | BRAFV600-mutated |
NCT03091257 | Dabrafenib and/or Trametinib | Phase I | Ongoing | BRAF/KRAS/NRAS mutated |
NCT03312530 [68] | Cobimetinib + Venetoclax ± Atezolizumab | Phase I/II | ORR (≥PR) 27%/29% in the combination arms | - |
Guo et al. [66] | CH5126766 (VS-6766/ RO5126766) | Phase I | PR in 1/7 myeloma patients | Solid tumors and myeloma with RAS/RAF/MEK pathway mutations |
MyDRUG-trial (NCT03732703) | Cobimetinib + Dexamethasone + Ixazomib/Pomalidomide | Phase I/II Umbrella-trial | Ongoing | RAF/RAS-mutation |
TAPUR (NCT02693535) | Vemurafenib + Cobimetinib | Phase II Basket-trial | Ongoing | BRAFV600 E/D/K/R mutated |
CAPTUR (NCT03297606) | Vemurafenib + Cobimetinib | Phase II < Basket-trial | Ongoing | BRAF V600 mutated |
AKT-pathway | ||||
Richardson et al. [78] | Perifosine (+ Dexamethasone) | Phase II | 38% PR + MR after addition of dexamethasone | r/r MM |
Jakubowiak et al. [79] | Perifosine + Lenalidomide + Dexamethasone | Phase I | ORR (≥PR) 50% | r/r MM, no previous therapy with lenalidomide required |
Richardson et al. [80] | Perifosine + Bortezomib + Dexamethasone | Phase I/II | ORR (≥MR) 41%, 32% in bortezomib-refractory patients | r/r MM |
Richardson et al. [81] | Perifosine + Bortezomib + Dexamethasone | Phase III | ORR (≥PR) 20% vs. 27% in the placebo arm) | Phase III |
Spencer et al. [82] | Afuresertib | Phase I | ORR (≥PR) 8%, long median PFS in responding patients (319 days) | r/r MM |
Voorhees et al. [84] | Afuresertib + Bortezomib + Dexamethasone | Phase I/II | Preliminary data: ORR (≥PR) 41% in phase I part | r/r MM |
Tolcher et al. [88] | Trametinib + Afuresertib | Phase I/II | Discontinued due to toxicity | r/r MM, relapsed triple negative breast or endometrial cancer |
NCT01989598 | GSK2141795 + Trametinib | Phase II | Ongoing | r/r MM |
NCI MATCH | Capivasertib | Phase II | Ongoing | AKT-mutated |
Günther et al. [90] | Everolimus | Phase I | ORR (≥PR) 7% (1/15, maximum PFS 3 (months) | r/r MM |
Farag et al. [91] | Temsirolimus | Phase II | ORR (≥PR) 6% (1/16) | r/r MM |
Yee et al. [93] | Everolimus + Lenalidomide | Phase I | ORR (≥MR) 65% | r/r MM, no previous lenalidomide required |
Ghobrial et al. [92] | Temsirolimus + Bortezomib | Phase I/II | ≥PR 33% | r/r MM, no previous bortezomib required |
Ghobrial et al. [94] | Sapanisertip (TAK228) | Phase I | 1/31 myeloma patients with MR | r/r MM |
PIM-kinase pathway | ||||
Raab et al. [105] | PIM 447(LGH447) | Phase I | ORR (≥PR) 9%, disease control rate 72%, median PFS 10.9 months | r/r MM |
NCT02144038 | PIM 447(LGH447) + BYL719 | Phase I/II | Discontinued due to toxicity | r/r MM |
c-MYC pathway | ||||
Amorim et al. [118] | OTX015 | Phase I | No activity in the myeloma group | r/r MM, lymphoma |
NCT02157636 | CPI-0610 | Phase I | Ongoing | r/r MM |
NCT03068351 [119] | RO6870810 + Daratumumab | Phase I | ORR (≥PR) 16.7% | r/r MM, no previous daratumumab required |
Tolcher et al. [128] | DCR-MYC | Phase I | No published results available | r/r MM, advanced solid tumors, lymphoma |
p53 pathway | ||||
NCT02633059 | Idasanutlin + Ixazomib + Dexamethasone | Phase I/II | No published results available | r/r MM with del17p |
NCT03031730 | KRT-232 (AMG232) + Carfilzomib + Lenalidomide + Dexamethasone | Phase I | ongoing | r/r MM |
Strassz et al. [150] | HDP-101 | Phase I/II | Due to start Q1/2021 | r/r MM |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
John, L.; Krauth, M.T.; Podar, K.; Raab, M.-S. Pathway-Directed Therapy in Multiple Myeloma. Cancers 2021, 13, 1668. https://doi.org/10.3390/cancers13071668
John L, Krauth MT, Podar K, Raab M-S. Pathway-Directed Therapy in Multiple Myeloma. Cancers. 2021; 13(7):1668. https://doi.org/10.3390/cancers13071668
Chicago/Turabian StyleJohn, Lukas, Maria Theresa Krauth, Klaus Podar, and Marc-Steffen Raab. 2021. "Pathway-Directed Therapy in Multiple Myeloma" Cancers 13, no. 7: 1668. https://doi.org/10.3390/cancers13071668
APA StyleJohn, L., Krauth, M. T., Podar, K., & Raab, M. -S. (2021). Pathway-Directed Therapy in Multiple Myeloma. Cancers, 13(7), 1668. https://doi.org/10.3390/cancers13071668