Overcoming Acquired Drug Resistance to Cancer Therapies through Targeted STAT3 Inhibition
Abstract
:1. Introduction
2. STATs (Signal Transducer and Activators of Transcription)
3. The Role of STAT3 in Cell Cycle Arrest and Regulation
4. ADR Development to Chemotherapeutics
5. ADR Development to Targeted Therapies
6. ADR Development to Monoclonal Antibody Treatment
7. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Floros, K.V.; Hata, A.N.; Faber, A.C. Investigating New Mechanisms of Acquired Resistance to Targeted Therapies: If You Hit Them Harder, Do They Get Up Differently? Cancer Res. 2020, 80, 25–26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rebe, C.; Ghiringhelli, F. STAT3, a Master Regulator of Anti-Tumor Immune Response. Cancers 2019, 11, 1280. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vogelstein, B.; Papadopoulos, N.; Velculescu, V.E.; Zhou, S.; Diaz, L.A., Jr.; Kinzler, K.W. Cancer genome landscapes. Science 2013, 339, 1546–1558. [Google Scholar] [CrossRef] [PubMed]
- Cao, W.; Liu, Y.; Zhang, R.; Zhang, B.; Wang, T.; Zhu, X.; Mei, L.; Chen, H.; Zhang, H.; Ming, P.; et al. Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells. Sci. Rep. 2015, 5, 8477. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chen, Y.; Li, F.; Li, D.; Liu, W.; Zhang, L. Atezolizumab and blockade of LncRNA PVT1 attenuate cisplatin resistant ovarian cancer cells progression synergistically via JAK2/STAT3/PD-L1 pathway. Clin. Immunol. 2021, 227, 108728. [Google Scholar] [CrossRef]
- Chiu, H.C.; Chou, D.L.; Huang, C.T.; Lin, W.H.; Lien, T.W.; Yen, K.J.; Hsu, J.T. Suppression of Stat3 activity sensitizes gefitinib-resistant non small cell lung cancer cells. Biochem. Pharmacol. 2011, 81, 1263–1270. [Google Scholar] [CrossRef]
- Hartsough, E.J.; Aplin, A.E. A STATement on vemurafenib-resistant melanoma. J. Investig. Dermatol. 2013, 133, 1928–1929. [Google Scholar] [CrossRef] [Green Version]
- Hatiboglu, M.A.; Kong, L.Y.; Wei, J.; Wang, Y.; McEnery, K.A.; Fuller, G.N.; Qiao, W.; Davies, M.A.; Priebe, W.; Heimberger, A.B. The tumor microenvironment expression of p-STAT3 influences the efficacy of cyclophosphamide with WP1066 in murine melanoma models. Int. J. Cancer 2012, 131, 8–17. [Google Scholar] [CrossRef] [Green Version]
- Huang, W.C.; Hung, C.M.; Wei, C.T.; Chen, T.M.; Chien, P.H.; Pan, H.L.; Lin, Y.M.; Chen, Y.J. Interleukin-6 expression contributes to lapatinib resistance through maintenance of stemness property in HER2-positive breast cancer cells. Oncotarget 2016, 7, 62352–62363. [Google Scholar] [CrossRef] [Green Version]
- Huser, L.; Kokkaleniou, M.M.; Granados, K.; Dworacek, J.; Federico, A.; Vierthaler, M.; Novak, D.; Arkhypov, I.; Hielscher, T.; Umansky, V.; et al. HER3-Receptor-Mediated STAT3 Activation Plays a Central Role in Adaptive Resistance toward Vemurafenib in Melanoma. Cancers 2020, 12, 3761. [Google Scholar] [CrossRef]
- Li, C.; Zang, Y.; Sen, M.; Leeman-Neill, R.J.; Man, D.S.; Grandis, J.R.; Johnson, D.E. Bortezomib up-regulates activated signal transducer and activator of transcription-3 and synergizes with inhibitors of signal transducer and activator of transcription-3 to promote head and neck squamous cell carcinoma cell death. Mol. Cancer Ther. 2009, 8, 2211–2220. [Google Scholar] [CrossRef] [Green Version]
- Liao, Q.; Feng, X.; Li, X.; Chen, G.; Chen, J.; Yang, B.; Li, K.; Ai, J. Lapatinib-induced inhibition of ovarian function is counteracted by the STAT3 pathway both in vivo and in vitro. Oncol. Rep. 2020, 44, 1127–1135. [Google Scholar] [CrossRef] [PubMed]
- Liu, F.; Cao, J.; Wu, J.; Sullivan, K.; Shen, J.; Ryu, B.; Xu, Z.; Wei, W.; Cui, R. Stat3-targeted therapies overcome the acquired resistance to vemurafenib in melanomas. J. Investig. Dermatol. 2013, 133, 2041–2049. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, Z.; Ma, L.; Sun, Y.; Yu, W.; Wang, X. Targeting STAT3 signaling overcomes gefitinib resistance in non-small cell lung cancer. Cell Death Dis. 2021, 12, 561. [Google Scholar] [CrossRef] [PubMed]
- Manni, S.; Brancalion, A.; Mandato, E.; Tubi, L.Q.; Colpo, A.; Pizzi, M.; Cappellesso, R.; Zaffino, F.; Di Maggio, S.A.; Cabrelle, A.; et al. Protein kinase CK2 inhibition down modulates the NF-kappaB and STAT3 survival pathways, enhances the cellular proteotoxic stress and synergistically boosts the cytotoxic effect of bortezomib on multiple myeloma and mantle cell lymphoma cells. PLoS ONE 2013, 8, e75280. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mencalha, A.L.; Correa, S.; Salles, D.; Du Rocher, B.; Santiago, M.F.; Abdelhay, E. Inhibition of STAT3-interacting protein 1 (STATIP1) promotes STAT3 transcriptional up-regulation and imatinib mesylate resistance in the chronic myeloid leukemia. BMC Cancer 2014, 14, 866. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sayed, D.; Badrawy, H.; Gaber, N.; Khalaf, M.R. p-Stat3 and bcr/abl gene expression in chronic myeloid leukemia and their relation to imatinib therapy. Leuk. Res. 2014, 38, 243–250. [Google Scholar] [CrossRef] [PubMed]
- Sinnberg, T.; Makino, E.; Krueger, M.A.; Velic, A.; Macek, B.; Rothbauer, U.; Groll, N.; Potz, O.; Czemmel, S.; Niessner, H.; et al. A Nexus Consisting of Beta-Catenin and Stat3 Attenuates BRAF Inhibitor Efficacy and Mediates Acquired Resistance to Vemurafenib. EBioMedicine 2016, 8, 132–149. [Google Scholar] [CrossRef] [Green Version]
- Song, X.; Tang, W.; Peng, H.; Qi, X.; Li, J. FGFR leads to sustained activation of STAT3 to mediate resistance to EGFR-TKIs treatment. Investig. New Drugs 2021, 39, 1201–1212. [Google Scholar] [CrossRef]
- Vangala, J.R.; Dudem, S.; Jain, N.; Kalivendi, S.V. Regulation of PSMB5 protein and beta subunits of mammalian proteasome by constitutively activated signal transducer and activator of transcription 3 (STAT3): Potential role in bortezomib-mediated anticancer therapy. J. Biol. Chem. 2014, 289, 12612–12622. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, X.; Goldstein, D.; Crowe, P.J.; Yang, M.; Garrett, K.; Zeps, N.; Yang, J.L. Overcoming resistance of targeted EGFR monotherapy by inhibition of STAT3 escape pathway in soft tissue sarcoma. Oncotarget 2016, 7, 21496–21509. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, K.; Chang, Q.; Lu, Y.; Qiu, P.; Chen, B.; Thakur, C.; Sun, J.; Li, L.; Kowluru, A.; Chen, F. Gefitinib resistance resulted from STAT3-mediated Akt activation in lung cancer cells. Oncotarget 2013, 4, 2430–2438. [Google Scholar] [CrossRef] [Green Version]
- Yang, M.H.; Jung, S.H.; Chinnathambi, A.; Alahmadi, T.A.; Alharbi, S.A.; Sethi, G.; Ahn, K.S. Attenuation of STAT3 Signaling Cascade by Daidzin Can Enhance the Apoptotic Potential of Bortezomib against Multiple Myeloma. Biomolecules 2019, 10, 23. [Google Scholar] [CrossRef] [Green Version]
- Yao, Y.; Sun, Y.; Shi, M.; Xia, D.; Zhao, K.; Zeng, L.; Yao, R.; Zhang, Y.; Li, Z.; Niu, M.; et al. Piperlongumine induces apoptosis and reduces bortezomib resistance by inhibiting STAT3 in multiple myeloma cells. Oncotarget 2016, 7, 73497–73508. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, W.W.; Cortes, J.E.; Yao, H.; Zhang, L.; Reddy, N.G.; Jabbour, E.; Kantarjian, H.M.; Jones, D. Predictors of primary imatinib resistance in chronic myelogenous leukemia are distinct from those in secondary imatinib resistance. J. Clin. Oncol. 2009, 27, 3642–3649. [Google Scholar] [CrossRef] [Green Version]
- Zhang, Z.; Wang, W.; Ma, D.; Xiong, J.; Kuang, X.; Zhang, S.; Fang, Q.; Wang, J. Heme oxygenase-1 inhibition mediates Gas6 to enhance bortezomib-sensitivity in multiple myeloma via ERK/STAT3 axis. Aging 2020, 12, 6611–6629. [Google Scholar] [CrossRef]
- Zheng, Q.; Dong, H.; Mo, J.; Zhang, Y.; Huang, J.; Ouyang, S.; Shi, S.; Zhu, K.; Qu, X.; Hu, W.; et al. A novel STAT3 inhibitor W2014-S regresses human non-small cell lung cancer xenografts and sensitizes EGFR-TKI acquired resistance. Theranostics 2021, 11, 824–840. [Google Scholar] [CrossRef]
- Berman, H.; Henrick, K.; Nakamura, H. Announcing the worldwide Protein Data Bank. Nat. Struct. Biol. 2003, 10, 980. [Google Scholar] [CrossRef]
- Byun, W.S.; Bae, E.S.; Cui, J.; Park, H.J.; Oh, D.C.; Lee, S.K. Antitumor Activity of Pulvomycin via Targeting Activated-STAT3 Signaling in Docetaxel-Resistant Triple-Negative Breast Cancer Cells. Biomedicines 2021, 9, 436. [Google Scholar] [CrossRef]
- Chen, D.; Ma, Y.; Li, P.; Liu, M.; Fang, Y.; Zhang, J.; Zhang, B.; Hui, Y.; Yin, Y. Piperlongumine Induces Apoptosis and Synergizes with Doxorubicin by Inhibiting the JAK2-STAT3 Pathway in Triple-Negative Breast Cancer. Molecules 2019, 24, 2338. [Google Scholar] [CrossRef] [Green Version]
- Di Sotto, A.; Di Giacomo, S.; Rubini, E.; Macone, A.; Gulli, M.; Mammola, C.L.; Eufemi, M.; Mancinelli, R.; Mazzanti, G. Modulation of STAT3 Signaling, Cell Redox Defenses and Cell Cycle Checkpoints by beta-Caryophyllene in Cholangiocarcinoma Cells: Possible Mechanisms Accounting for Doxorubicin Chemosensitization and Chemoprevention. Cells 2020, 9, 858. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, C.; Xing, H.; Guo, C.; Yang, Z.; Wang, Y.; Wang, Y. MiR-124 reversed the doxorubicin resistance of breast cancer stem cells through STAT3/HIF-1 signaling pathways. Cell Cycle 2019, 18, 2215–2227. [Google Scholar] [CrossRef]
- Wu, X.; Xiao, H.; Wang, R.; Liu, L.; Li, C.; Lin, J. Persistent GP130/STAT3 Signaling Contributes to the Resistance of Doxorubicin, Cisplatin, and MEK Inhibitor in Human Rhabdomyosarcoma Cells. Curr. Cancer Drug Targets 2016, 16, 631–638. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gong, J.; Munoz, A.R.; Pingali, S.; Payton-Stewart, F.; Chan, D.E.; Freeman, J.W.; Ghosh, R.; Kumar, A.P. Downregulation of STAT3/NF-kappaB potentiates gemcitabine activity in pancreatic cancer cells. Mol. Carcinog. 2017, 56, 402–411. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Guo, Y.; Xiao, Y.; Guo, H.; Zhu, H.; Chen, D.; Wang, J.; Deng, J.; Lan, J.; Liu, X.; Zhang, Q.; et al. The anti-dysenteric drug fraxetin enhances anti-tumor efficacy of gemcitabine and suppresses pancreatic cancer development by antagonizing STAT3 activation. Aging 2021, 13, 18545–18563. [Google Scholar] [CrossRef]
- Ioannou, N.; Seddon, A.M.; Dalgleish, A.; Mackintosh, D.; Solca, F.; Modjtahedi, H. Acquired resistance of pancreatic cancer cells to treatment with gemcitabine and HER-inhibitors is accompanied by increased sensitivity to STAT3 inhibition. Int. J. Oncol. 2016, 48, 908–918. [Google Scholar] [CrossRef] [Green Version]
- Lankadasari, M.B.; Aparna, J.S.; Mohammed, S.; James, S.; Aoki, K.; Binu, V.S.; Nair, S.; Harikumar, K.B. Targeting S1PR1/STAT3 loop abrogates desmoplasia and chemosensitizes pancreatic cancer to gemcitabine. Theranostics 2018, 8, 3824–3840. [Google Scholar] [CrossRef]
- Luo, F.; Lu, F.T.; Qiu, M.Z.; Zhou, T.; Ma, W.J.; Luo, M.; Zeng, K.M.; Luo, Q.Y.; Pan, W.T.; Zhang, L.; et al. Gemcitabine and APG-1252, a novel small molecule inhibitor of BCL-2/BCL-XL, display a synergistic antitumor effect in nasopharyngeal carcinoma through the JAK-2/STAT3/MCL-1 signaling pathway. Cell Death Dis. 2021, 12, 772. [Google Scholar] [CrossRef]
- Nagaraj, N.S.; Washington, M.K.; Merchant, N.B. Combined blockade of Src kinase and epidermal growth factor receptor with gemcitabine overcomes STAT3-mediated resistance of inhibition of pancreatic tumor growth. Clin. Cancer Res. 2011, 17, 483–493. [Google Scholar] [CrossRef] [Green Version]
- Nagathihalli, N.S.; Castellanos, J.A.; Shi, C.; Beesetty, Y.; Reyzer, M.L.; Caprioli, R.; Chen, X.; Walsh, A.J.; Skala, M.C.; Moses, H.L.; et al. Signal Transducer and Activator of Transcription 3, Mediated Remodeling of the Tumor Microenvironment Results in Enhanced Tumor Drug Delivery in a Mouse Model of Pancreatic Cancer. Gastroenterology 2015, 149, 1932–1943.e9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Venkatasubbarao, K.; Peterson, L.; Zhao, S.; Hill, P.; Cao, L.; Zhou, Q.; Nawrocki, S.T.; Freeman, J.W. Inhibiting signal transducer and activator of transcription-3 increases response to gemcitabine and delays progression of pancreatic cancer. Mol. Cancer 2013, 12, 104. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, X.; Tang, W.; Marquez, R.T.; Li, K.; Highfill, C.A.; He, F.; Lian, J.; Lin, J.; Fuchs, J.R.; Ji, M.; et al. Overcoming chemo/radio-resistance of pancreatic cancer by inhibiting STAT3 signaling. Oncotarget 2016, 7, 11708–11723. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhao, T.; Jin, F.; Xiao, D.; Wang, H.; Huang, C.; Wang, X.; Gao, S.; Liu, J.; Yang, S.; Hao, J. IL-37/ STAT3/ HIF-1alpha negative feedback signaling drives gemcitabine resistance in pancreatic cancer. Theranostics 2020, 10, 4088–4100. [Google Scholar] [CrossRef]
- Chang, W.M.; Chang, Y.C.; Yang, Y.C.; Lin, S.K.; Chang, P.M.; Hsiao, M. AKR1C1 controls cisplatin-resistance in head and neck squamous cell carcinoma through cross-talk with the STAT1/3 signaling pathway. J. Exp. Clin. Cancer Res. 2019, 38, 245. [Google Scholar] [CrossRef] [Green Version]
- Chen, K.B.; Yang, W.; Xuan, Y.; Lin, A.J. miR-526b-3p inhibits lung cancer cisplatin-resistance and metastasis by inhibiting STAT3-promoted PD-L1. Cell Death Dis. 2021, 12, 748. [Google Scholar] [CrossRef]
- Fan, H.; Ou, Q.; Su, Q.; Li, G.; Deng, Z.; Huang, X.; Bi, J. ZIPK activates the IL-6/STAT3 signaling pathway and promotes cisplatin resistance in gastric cancer cells. FEBS Open Bio 2021, 11, 2655–2667. [Google Scholar] [CrossRef]
- Jin, P.; Liu, Y.; Wang, R. STAT3 regulated miR-216a promotes ovarian cancer proliferation and cisplatin resistance. Biosci. Rep. 2018, 38, BSR20180547. [Google Scholar] [CrossRef]
- Kuo, W.Y.; Hwu, L.; Wu, C.Y.; Lee, J.S.; Chang, C.W.; Liu, R.S. STAT3/NF-kappaB-Regulated Lentiviral TK/GCV Suicide Gene Therapy for Cisplatin-Resistant Triple-Negative Breast Cancer. Theranostics 2017, 7, 647–663. [Google Scholar] [CrossRef] [Green Version]
- Lin, C.C.; Yeh, H.H.; Huang, W.L.; Yan, J.J.; Lai, W.W.; Su, W.P.; Chen, H.H.; Su, W.C. Metformin enhances cisplatin cytotoxicity by suppressing signal transducer and activator of transcription-3 activity independently of the liver kinase B1-AMP-activated protein kinase pathway. Am. J. Respir. Cell Mol. Biol. 2013, 49, 241–250. [Google Scholar] [CrossRef]
- Liu, W.H.; Chen, M.T.; Wang, M.L.; Lee, Y.Y.; Chiou, G.Y.; Chien, C.S.; Huang, P.I.; Chen, Y.W.; Huang, M.C.; Chiou, S.H.; et al. Cisplatin-selected resistance is associated with increased motility and stem-like properties via activation of STAT3/Snail axis in atypical teratoid/rhabdoid tumor cells. Oncotarget 2015, 6, 1750–1768. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sun, C.Y.; Nie, J.; Huang, J.P.; Zheng, G.J.; Feng, B. Targeting STAT3 inhibition to reverse cisplatin resistance. Biomed. Pharmacother. 2019, 117, 109135. [Google Scholar] [CrossRef]
- Tan, W.X.; Sun, G.; Shangguan, M.Y.; Gui, Z.; Bao, Y.; Li, Y.F.; Jia, Z.H. Novel role of lncRNA CHRF in cisplatin resistance of ovarian cancer is mediated by miR-10b induced EMT and STAT3 signaling. Sci. Rep. 2020, 10, 14768. [Google Scholar] [CrossRef] [PubMed]
- Tao, L.; Huang, G.; Wang, R.; Pan, Y.; He, Z.; Chu, X.; Song, H.; Chen, L. Cancer-associated fibroblasts treated with cisplatin facilitates chemoresistance of lung adenocarcinoma through IL-11/IL-11R/STAT3 signaling pathway. Sci. Rep. 2016, 6, 38408. [Google Scholar] [CrossRef]
- Zhu, X.; Shen, H.; Yin, X.; Long, L.; Chen, X.; Feng, F.; Liu, Y.; Zhao, P.; Xu, Y.; Li, M.; et al. IL-6R/STAT3/miR-204 feedback loop contributes to cisplatin resistance of epithelial ovarian cancer cells. Oncotarget 2017, 8, 39154–39166. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Filppu, P.; Tanjore Ramanathan, J.; Granberg, K.J.; Gucciardo, E.; Haapasalo, H.; Lehti, K.; Nykter, M.; Le Joncour, V.; Laakkonen, P. CD109-GP130 interaction drives glioblastoma stem cell plasticity and chemoresistance through STAT3 activity. JCI Insight 2021, 6. [Google Scholar] [CrossRef] [PubMed]
- Kohsaka, S.; Wang, L.; Yachi, K.; Mahabir, R.; Narita, T.; Itoh, T.; Tanino, M.; Kimura, T.; Nishihara, H.; Tanaka, S. STAT3 inhibition overcomes temozolomide resistance in glioblastoma by downregulating MGMT expression. Mol. Cancer Ther. 2012, 11, 1289–1299. [Google Scholar] [CrossRef] [Green Version]
- Lee, E.S.; Ko, K.K.; Joe, Y.A.; Kang, S.G.; Hong, Y.K. Inhibition of STAT3 reverses drug resistance acquired in temozolomide-resistant human glioma cells. Oncol. Lett. 2011, 2, 115–121. [Google Scholar] [CrossRef] [Green Version]
- Xu, P.; Wang, H.; Pan, H.; Chen, J.; Deng, C. Anlotinib combined with temozolomide suppresses glioblastoma growth via mediation of JAK2/STAT3 signaling pathway. Cancer Chemother. Pharmacol. 2022, 89, 183–196. [Google Scholar] [CrossRef]
- Vengoji, R.; Macha, M.A.; Nimmakayala, R.K.; Rachagani, S.; Siddiqui, J.A.; Mallya, K.; Gorantla, S.; Jain, M.; Ponnusamy, M.P.; Batra, S.K.; et al. Afatinib and Temozolomide combination inhibits tumorigenesis by targeting EGFRvIII-cMet signaling in glioblastoma cells. J. Exp. Clin. Cancer Res. 2019, 38, 266. [Google Scholar] [CrossRef]
- Ding, Y.; Zhen, Z.; Nisar, M.A.; Ali, F.; Din, R.U.; Khan, M.; Mughal, T.A.; Alam, G.; Liu, L.; Saleem, M.Z. Sesquiterpene Lactones Attenuate Paclitaxel Resistance Via Inhibiting MALAT1/STAT3/ FUT4 Axis and P-Glycoprotein Transporters in Lung Cancer Cells. Front. Pharmacol. 2022, 13, 795613. [Google Scholar] [CrossRef] [PubMed]
- Wang, L.; Zhang, F.; Cui, J.Y.; Chen, L.; Chen, Y.T.; Liu, B.W. CAFs enhance paclitaxel resistance by inducing EMT through the IL-6/JAK2/STAT3 pathway. Oncol. Rep. 2018, 39, 2081–2090. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, S.; Yao, Y.; Yao, M.; Fu, P.; Wang, W. Interleukin-22 promotes triple negative breast cancer cells migration and paclitaxel resistance through JAK-STAT3/MAPKs/AKT signaling pathways. Biochem. Biophys. Res. Commun. 2018, 503, 1605–1609. [Google Scholar] [CrossRef] [PubMed]
- Xu, Y.; Zhang, J.; Wu, J.; Zhong, S.; Li, H. Inhibition of JAK2 Reverses Paclitaxel Resistance in Human Ovarian Cancer Cells. Int. J. Gynecol. Cancer 2015, 25, 1557–1564. [Google Scholar] [CrossRef] [PubMed]
- Zhao, C.; Chen, H.Y.; Zhao, F.; Feng, H.J.; Su, J.P. Acylglycerol kinase promotes paclitaxel resistance in nasopharyngeal carcinoma cells by regulating FOXM1 via the JAK2/STAT3 pathway. Cytokine 2021, 148, 155595. [Google Scholar] [CrossRef]
- Kim, S.M.; Kwon, O.J.; Hong, Y.K.; Kim, J.H.; Solca, F.; Ha, S.J.; Soo, R.A.; Christensen, J.G.; Lee, J.H.; Cho, B.C. Activation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation. Mol. Cancer Ther. 2012, 11, 2254–2264. [Google Scholar] [CrossRef] [Green Version]
- Shu, D.; Xu, Y.; Chen, W. Knockdown of lncRNA BLACAT1 reverses the resistance of afatinib to non-small cell lung cancer via modulating STAT3 signalling. J. Drug Target 2020, 28, 300–306. [Google Scholar] [CrossRef]
- Cuyas, E.; Perez-Sanchez, A.; Micol, V.; Menendez, J.A.; Bosch-Barrera, J. STAT3-targeted treatment with silibinin overcomes the acquired resistance to crizotinib in ALK-rearranged lung cancer. Cell Cycle 2016, 15, 3413–3418. [Google Scholar] [CrossRef] [Green Version]
- Dosch, A.R.; Dai, X.; Reyzer, M.L.; Mehra, S.; Srinivasan, S.; Willobee, B.A.; Kwon, D.; Kashikar, N.; Caprioli, R.; Merchant, N.B.; et al. Combined Src/EGFR Inhibition Targets STAT3 Signaling and Induces Stromal Remodeling to Improve Survival in Pancreatic Cancer. Mol. Cancer Res. 2020, 18, 623–631. [Google Scholar] [CrossRef] [Green Version]
- Harada, D.; Takigawa, N.; Kiura, K. The Role of STAT3 in Non-Small Cell Lung Cancer. Cancers 2014, 6, 708–722. [Google Scholar] [CrossRef] [Green Version]
- Li, R.; Hu, Z.; Sun, S.Y.; Chen, Z.G.; Owonikoko, T.K.; Sica, G.L.; Ramalingam, S.S.; Curran, W.J.; Khuri, F.R.; Deng, X. Niclosamide overcomes acquired resistance to erlotinib through suppression of STAT3 in non-small cell lung cancer. Mol. Cancer Ther. 2013, 12, 2200–2212. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Salzberg, M.P.; Merchant, N.B. Overcoming erlotinib resistance with STAT3 inhibition in pancreatic cancer. J. Clin. Oncol. 2017, 35, 304. [Google Scholar] [CrossRef]
- Stanam, A.; Love-Homan, L.; Joseph, T.S.; Espinosa-Cotton, M.; Simons, A.L. Upregulated interleukin-6 expression contributes to erlotinib resistance in head and neck squamous cell carcinoma. Mol. Oncol. 2015, 9, 1371–1383. [Google Scholar] [CrossRef] [Green Version]
- Tang, C.H.; Qin, L.; Gao, Y.C.; Chen, T.Y.; Xu, K.; Liu, T.; Ren, T. APE1 shRNA-loaded cancer stem cell-derived extracellular vesicles reverse Erlotinib resistance in non-small cell lung cancer via the IL-6/STAT3 signalling. Clin. Transl. Med. 2022, 12, e876. [Google Scholar] [CrossRef]
- Iguchi, T.; Tamada, S.; Kato, M.; Yasuda, S.; Yamasaki, T.; Nakatani, T. Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: Study protocol for a multicenter randomized phase II trial (the OCUU-CRPC study). BMC Cancer 2019, 19, 339. [Google Scholar] [CrossRef] [PubMed]
- Giacinti, S.; Poti, G.; Roberto, M.; Macrini, S.; Bassanelli, M.; Di Pietro, F.; Aschelter, A.M.; Ceribelli, A.; Ruggeri, E.M.; Marchetti, P. Molecular Basis of Drug Resistance and Insights for New Treatment Approaches in mCRPC. Anticancer Res. 2018, 38, 6029–6039. [Google Scholar] [CrossRef]
- Schroeder, A.; Herrmann, A.; Cherryholmes, G.; Kowolik, C.; Buettner, R.; Pal, S.; Yu, H.; Muller-Newen, G.; Jove, R. Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling. Cancer Res. 2014, 74, 1227–1237. [Google Scholar] [CrossRef] [Green Version]
- Liu, C.; Zhu, Y.; Lou, W.; Cui, Y.; Evans, C.P.; Gao, A.C. Inhibition of constitutively active Stat3 reverses enzalutamide resistance in LNCaP derivative prostate cancer cells. Prostate 2014, 74, 201–209. [Google Scholar] [CrossRef] [Green Version]
- Liu, Q.; Tong, D.; Liu, G.; Xu, J.; Do, K.; Geary, K.; Zhang, D.; Zhang, J.; Zhang, Y.; Li, Y.; et al. Metformin reverses prostate cancer resistance to enzalutamide by targeting TGF-beta1/STAT3 axis-regulated EMT. Cell Death Dis. 2017, 8, e3007. [Google Scholar] [CrossRef] [Green Version]
- Yao, J.; Deng, K.; Huang, J.; Zeng, R.; Zuo, J. Progress in the Understanding of the Mechanism of Tamoxifen Resistance in Breast Cancer. Front. Pharmacol. 2020, 11, 592912. [Google Scholar] [CrossRef]
- Lv, C.; Huang, Y.; Huang, R.; Wang, Q.; Zhang, H.; Jin, J.; Lu, D.; Zhou, Y.; Shen, Y.; Zhang, W.; et al. Narciclasine targets STAT3 via distinct mechanisms in tamoxifen-resistant breast cancer cells. Mol. Ther. Oncolytics 2022, 24, 340–354. [Google Scholar] [CrossRef]
- Moon, S.Y.; Lee, H.; Kim, S.; Hong, J.H.; Chun, S.H.; Lee, H.Y.; Kang, K.; Kim, H.S.; Won, H.S.; Ko, Y.H. Inhibition of STAT3 enhances sensitivity to tamoxifen in tamoxifen-resistant breast cancer cells. BMC Cancer 2021, 21, 931. [Google Scholar] [CrossRef] [PubMed]
- Zhu, N.; Zhang, J.; Du, Y.; Qin, X.; Miao, R.; Nan, J.; Chen, X.; Sun, J.; Zhao, R.; Zhang, X.; et al. Loss of ZIP facilitates JAK2-STAT3 activation in tamoxifen-resistant breast cancer. Proc. Natl. Acad. Sci. USA 2020, 117, 15047–15054. [Google Scholar] [CrossRef] [PubMed]
- Chen, W.; Shen, X.; Xia, X.; Xu, G.; Ma, T.; Bai, X.; Liang, T. NSC 74859-mediated inhibition of STAT3 enhances the anti-proliferative activity of cetuximab in hepatocellular carcinoma. Liver Int. 2012, 32, 70–77. [Google Scholar] [CrossRef] [PubMed]
- O’Keefe, R.A.; Bhola, N.E.; Lee, D.S.; Johnson, D.E.; Grandis, J.R. Interleukin 6 is increased in preclinical HNSCC models of acquired cetuximab resistance, but is not required for maintenance of resistance. PLoS ONE 2020, 15, e0227261. [Google Scholar] [CrossRef] [PubMed]
- Willey, C.D.; Anderson, J.C.; Trummell, H.Q.; Naji, F.; de Wijn, R.; Yang, E.S.; Bredel, M.; Thudi, N.K.; Bonner, J.A. Differential escape mechanisms in cetuximab-resistant head and neck cancer cells. Biochem. Biophys. Res. Commun. 2019, 517, 36–42. [Google Scholar] [CrossRef]
- Eichten, A.; Su, J.; Adler, A.P.; Zhang, L.; Ioffe, E.; Parveen, A.A.; Yancopoulos, G.D.; Rudge, J.; Lowy, I.; Lin, H.C.; et al. Resistance to Anti-VEGF Therapy Mediated by Autocrine IL6/STAT3 Signaling and Overcome by IL6 Blockade. Cancer Res. 2016, 76, 2327–2339. [Google Scholar] [CrossRef] [Green Version]
- Jiang, L.; Ren, L.; Chen, H.; Pan, J.; Zhang, Z.; Kuang, X.; Chen, X.; Bao, W.; Lin, C.; Zhou, Z.; et al. NCAPG confers trastuzumab resistance via activating SRC/STAT3 signaling pathway in HER2-positive breast cancer. Cell Death Dis. 2020, 11, 547. [Google Scholar] [CrossRef]
- Li, G.; Zhao, L.; Li, W.; Fan, K.; Qian, W.; Hou, S.; Wang, H.; Dai, J.; Wei, H.; Guo, Y. Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression. Oncotarget 2014, 5, 8317–8329. [Google Scholar] [CrossRef] [Green Version]
- Wang, L.; Wang, Q.; Gao, M.; Fu, L.; Li, Y.; Quan, H.; Lou, L. STAT3 activation confers trastuzumab-emtansine (T-DM1) resistance in HER2-positive breast cancer. Cancer Sci. 2018, 109, 3305–3315. [Google Scholar] [CrossRef] [Green Version]
- Yang, Z.; Guo, L.; Liu, D.; Sun, L.; Chen, H.; Deng, Q.; Liu, Y.; Yu, M.; Ma, Y.; Guo, N.; et al. Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop. Oncotarget 2015, 6, 5072–5087. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chehrazi-Raffle, A.; Meza, L.; Alcantara, M.; Dizman, N.; Bergerot, P.; Salgia, N.; Hsu, J.; Ruel, N.; Salgia, S.; Malhotra, J.; et al. Circulating cytokines associated with clinical response to systemic therapy in metastatic renal cell carcinoma. J. Immunother. Cancer 2021, 9. [Google Scholar] [CrossRef] [PubMed]
- Datta, J.; Dai, X.; Bianchi, A.; De Castro Silva, I.; Mehra, S.; Garrido, V.T.; Lamichhane, P.; Singh, S.P.; Zhou, Z.; Dosch, A.R.; et al. Combined MEK and STAT3 Inhibition Uncovers Stromal Plasticity by Enriching for Cancer-Associated Fibroblasts With Mesenchymal Stem Cell-Like Features to Overcome Immunotherapy Resistance in Pancreatic Cancer. Gastroenterology 2022, 163, 1593–1612. [Google Scholar] [CrossRef]
- Fang, W.; Zhang, J.; Hong, S.; Zhan, J.; Chen, N.; Qin, T.; Tang, Y.; Zhang, Y.; Kang, S.; Zhou, T.; et al. EBV-driven LMP1 and IFN-gamma up-regulate PD-L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy. Oncotarget 2014, 5, 12189–12202. [Google Scholar] [CrossRef] [PubMed]
- Hou, J.; Zhao, R.; Xia, W.; Chang, C.W.; You, Y.; Hsu, J.M.; Nie, L.; Chen, Y.; Wang, Y.C.; Liu, C.; et al. PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. Nat.Cell Biol. 2020, 22, 1264–1275. [Google Scholar] [CrossRef] [PubMed]
- Huang, L.; Xu, Y.; Fang, J.; Liu, W.; Chen, J.; Liu, Z.; Xu, Q. Targeting STAT3 Abrogates Tim-3 Upregulation of Adaptive Resistance to PD-1 Blockade on Regulatory T Cells of Melanoma. Front. Immunol. 2021, 12, 654749. [Google Scholar] [CrossRef] [PubMed]
- Kalbasi, A.; Ribas, A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat. Rev. Immunol. 2020, 20, 25–39. [Google Scholar] [CrossRef]
- Kim, T.W.; Kim, Y.; Keum, H.; Jung, W.; Kang, M.; Jon, S. Combination of a STAT3 inhibitor with anti-PD-1 immunotherapy is an effective treatment regimen for a vemurafenib-resistant melanoma. Mol. Ther. Oncolytics 2022, 26, 1–14. [Google Scholar] [CrossRef]
- MacManus, M.; Hegi-Johnson, F. Overcoming immunotherapy resistance in NSCLC. Lancet Oncol. 2022, 23, 191–193. [Google Scholar] [CrossRef]
- Marzec, M.; Zhang, Q.; Goradia, A.; Raghunath, P.N.; Liu, X.; Paessler, M.; Wang, H.Y.; Wysocka, M.; Cheng, M.; Ruggeri, B.A.; et al. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc. Natl. Acad. Sci. USA 2008, 105, 20852–20857. [Google Scholar] [CrossRef] [Green Version]
- Reck, M.; Rodriguez-Abreu, D.; Robinson, A.G.; Hui, R.; Csoszi, T.; Fulop, A.; Gottfried, M.; Peled, N.; Tafreshi, A.; Cuffe, S.; et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2016, 375, 1823–1833. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Venkatraman, S.; Meller, J.; Hongeng, S.; Tohtong, R.; Chutipongtanate, S. Transcriptional Regulation of Cancer Immune Checkpoints: Emerging Strategies for Immunotherapy. Vaccines 2020, 8, 735. [Google Scholar] [CrossRef] [PubMed]
- Witt, K.; Evans-Axelsson, S.; Lundqvist, A.; Johansson, M.; Bjartell, A.; Hellsten, R. Inhibition of STAT3 augments antitumor efficacy of anti-CTLA-4 treatment against prostate cancer. Cancer Immunol. Immunother. 2021, 70, 3155–3166. [Google Scholar] [CrossRef] [PubMed]
- Woods, D.M.; Ramakrishnan, R.; Laino, A.S.; Berglund, A.; Walton, K.; Betts, B.C.; Weber, J.S. Decreased Suppression and Increased Phosphorylated STAT3 in Regulatory T Cells are Associated with Benefit from Adjuvant PD-1 Blockade in Resected Metastatic Melanoma. Clin. Cancer Res. 2018, 24, 6236–6247. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zou, S.; Tong, Q.; Liu, B.; Huang, W.; Tian, Y.; Fu, X. Targeting STAT3 in Cancer Immunotherapy. Mol. Cancer 2020, 19, 145. [Google Scholar] [CrossRef] [PubMed]
- You, W.; Liu, X.; Yu, Y.; Chen, C.; Xiong, Y.; Liu, Y.; Sun, Y.; Tan, C.; Zhang, H.; Wang, Y.; et al. miR-502-5p affects gastric cancer progression by targeting PD-L1. Cancer Cell Int. 2020, 20, 395. [Google Scholar] [CrossRef]
- McGowan, J.V.; Chung, R.; Maulik, A.; Piotrowska, I.; Walker, J.M.; Yellon, D.M. Anthracycline Chemotherapy and Cardiotoxicity. Cardiovasc. Drugs Ther. 2017, 31, 63–75. [Google Scholar] [CrossRef] [Green Version]
- Mohammadian, J.; Mahmoudi, S.; Pourmohammad, P.; Pirouzpanah, M.; Salehnia, F.; Maroufi, N.F.; Samadi, N.; Sabzichi, M. Formulation of Stattic as STAT3 inhibitor in nanostructured lipid carriers (NLCs) enhances efficacy of doxorubicin in melanoma cancer cells. Naunyn Schmiedebergs Arch. Pharmacol. 2020, 393, 2315–2323. [Google Scholar] [CrossRef]
- Schust, J.; Sperl, B.; Hollis, A.; Mayer, T.U.; Berg, T. Stattic: A small-molecule inhibitor of STAT3 activation and dimerization. Chem. Biol. 2006, 13, 1235–1242. [Google Scholar] [CrossRef] [Green Version]
- Gariboldi, M.B.; Ravizza, R.; Molteni, R.; Osella, D.; Gabano, E.; Monti, E. Inhibition of Stat3 increases doxorubicin sensitivity in a human metastatic breast cancer cell line. Cancer Lett. 2007, 258, 181–188. [Google Scholar] [CrossRef]
- Maryam, A.; Mehmood, T.; Zhang, H.; Li, Y.; Khan, M.; Ma, T. Alantolactone induces apoptosis, promotes STAT3 glutathionylation and enhances chemosensitivity of A549 lung adenocarcinoma cells to doxorubicin via oxidative stress. Sci. Rep. 2017, 7, 6242. [Google Scholar] [CrossRef] [Green Version]
- Sheng, H.; Feng, Q.; Quan, Q.; Sheng, X.; Zhang, P. Inhibition of STAT3 reverses Taxol-resistance in ovarian cancer by down-regulating G6PD expression in vitro. Biochem. Biophys. Res. Commun. 2022, 617, 62–68. [Google Scholar] [CrossRef] [PubMed]
- Fan, Z.; Cui, H.; Yu, H.; Ji, Q.; Kang, L.; Han, B.; Wang, J.; Dong, Q.; Li, Y.; Yan, Z.; et al. MiR-125a promotes paclitaxel sensitivity in cervical cancer through altering STAT3 expression. Oncogenesis 2016, 5, e223. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chuang, H.Y.; Su, Y.K.; Liu, H.W.; Chen, C.H.; Chiu, S.C.; Cho, D.Y.; Lin, S.Z.; Chen, Y.S.; Lin, C.M. Preclinical Evidence of STAT3 Inhibitor Pacritinib Overcoming Temozolomide Resistance via Downregulating miR-21-Enriched Exosomes from M2 Glioblastoma-Associated Macrophages. J. Clin. Med. 2019, 8, 959. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ouedraogo, Z.G.; Biau, J.; Kemeny, J.L.; Morel, L.; Verrelle, P.; Chautard, E. Role of STAT3 in Genesis and Progression of Human Malignant Gliomas. Mol. Neurobiol. 2017, 54, 5780–5797. [Google Scholar] [CrossRef]
- Zheng, H.; Yang, L.; Kang, Y.; Chen, M.; Lin, S.; Xiang, Y.; Li, C.; Dai, X.; Huang, X.; Liang, G.; et al. Alantolactone sensitizes human pancreatic cancer cells to EGFR inhibitors through the inhibition of STAT3 signaling. Mol. Carcinog. 2019, 58, 565–576. [Google Scholar] [CrossRef]
- Groner, B. Determinants of the extent and duration of STAT3 signaling. JAKSTAT 2012, 1, 211–215. [Google Scholar] [CrossRef] [Green Version]
- Wang, H.Q.; Man, Q.W.; Huo, F.Y.; Gao, X.; Lin, H.; Li, S.R.; Wang, J.; Su, F.C.; Cai, L.; Shi, Y.; et al. STAT3 pathway in cancers: Past, present, and future. MedComm (2020) 2022, 3, e124. [Google Scholar] [CrossRef]
- Gide, T.N.; Wilmott, J.S.; Scolyer, R.A.; Long, G.V. Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Metastatic Melanoma. Clin. Cancer Res. 2018, 24, 1260–1270. [Google Scholar] [CrossRef] [Green Version]
- Morselli, E.; Galluzzi, L.; Kepp, O.; Vicencio, J.M.; Criollo, A.; Maiuri, M.C.; Kroemer, G. Anti- and pro-tumor functions of autophagy. Biochim. Biophys. Acta 2009, 1793, 1524–1532. [Google Scholar] [CrossRef] [Green Version]
- You, L.; Wang, Z.; Li, H.; Shou, J.; Jing, Z.; Xie, J.; Sui, X.; Pan, H.; Han, W. The role of STAT3 in autophagy. Autophagy 2015, 11, 729–739. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, X.; Zhou, Y.; Li, Y.; Yang, L.; Ma, Y.; Peng, X.; Yang, S.; Liu, J.; Li, H. Autophagy: A novel mechanism of chemoresistance in cancers. Biomed. Pharmacother. 2019, 119, 109415. [Google Scholar] [CrossRef] [PubMed]
- Xu, J.; Zhang, J.; Mao, Q.F.; Wu, J.; Wang, Y. The Interaction Between Autophagy and JAK/STAT3 Signaling Pathway in Tumors. Front. Genet. 2022, 13, 880359. [Google Scholar] [CrossRef] [PubMed]
- Pu, Y.; Wang, J.; Wang, S. Role of autophagy in drug resistance and regulation of osteosarcoma (Review). Mol. Clin. Oncol. 2022, 16, 72. [Google Scholar] [CrossRef]
- Wu, L.; Shen, B.; Li, J.; Zhang, H.; Zhang, K.; Yang, Y.; Zu, Z.; Shen, D.; Luo, M. STAT3 exerts pro-tumor and anti-autophagy roles in cervical cancer. Diagn. Pathol. 2022, 17, 13. [Google Scholar] [CrossRef]
- Jiang, T.; Chen, X.; Ren, X.; Yang, J.M.; Cheng, Y. Emerging role of autophagy in anti-tumor immunity: Implications for the modulation of immunotherapy resistance. Drug Resist. Updat. 2021, 56, 100752. [Google Scholar] [CrossRef]
- Adeshakin, F.O.; Adeshakin, A.O.; Liu, Z.; Lu, X.; Cheng, J.; Zhang, P.; Yan, D.; Zhang, G.; Wan, X. Upregulation of V-ATPase by STAT3 Activation Promotes Anoikis Resistance and Tumor Metastasis. J. Cancer 2021, 12, 4819–4829. [Google Scholar] [CrossRef]
- Du, X.L.; Yang, H.; Liu, S.G.; Luo, M.L.; Hao, J.J.; Zhang, Y.; Lin, D.C.; Xu, X.; Cai, Y.; Zhan, Q.M.; et al. Calreticulin promotes cell motility and enhances resistance to anoikis through STAT3-CTTN-Akt pathway in esophageal squamous cell carcinoma. Oncogene 2009, 28, 3714–3722. [Google Scholar] [CrossRef] [Green Version]
- Fofaria, N.M.; Srivastava, S.K. STAT3 induces anoikis resistance, promotes cell invasion and metastatic potential in pancreatic cancer cells. Carcinogenesis 2015, 36, 142–150. [Google Scholar] [CrossRef] [Green Version]
- Huyen, N.T.; Prachayasittikul, V.; Chan-On, W. Anoikis-resistant cholangiocarcinoma cells display aggressive characteristics and increase STAT3 activation. J. Hepatobiliary Pancreat Sci. 2016, 23, 397–405. [Google Scholar] [CrossRef]
- Lin, Y.T.; Wang, H.C.; Hsu, Y.C.; Cho, C.L.; Yang, M.Y.; Chien, C.Y. Capsaicin Induces Autophagy and Apoptosis in Human Nasopharyngeal Carcinoma Cells by Downregulating the PI3K/AKT/mTOR Pathway. Int. J. Mol. Sci. 2017, 18, 1343. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Neiva, K.G.; Zhang, Z.; Miyazawa, M.; Warner, K.A.; Karl, E.; Nor, J.E. Cross talk initiated by endothelial cells enhances migration and inhibits anoikis of squamous cell carcinoma cells through STAT3/Akt/ERK signaling. Neoplasia 2009, 11, 583–593. [Google Scholar] [CrossRef] [PubMed]
- Wang, L.N.; Zhang, Z.T.; Wang, L.; Wei, H.X.; Zhang, T.; Zhang, L.M.; Lin, H.; Zhang, H.; Wang, S.Q. TGF-beta1/SH2B3 axis regulates anoikis resistance and EMT of lung cancer cells by modulating JAK2/STAT3 and SHP2/Grb2 signaling pathways. Cell Death Dis. 2022, 13, 472. [Google Scholar] [CrossRef] [PubMed]
- Tomida, M.; Ohtake, H.; Yokota, T.; Kobayashi, Y.; Kurosumi, M. Stat3 Up-Regulates Expression of Nicotinamide N-Methyltransferase in Human Cancer Cells. J. Cancer Res. Clin. Oncol. 2008, 134, 551–559. [Google Scholar] [CrossRef] [PubMed]
- Lu, S.; Ke, S.; Wang, C.; Xu, Y.; Li, Z.; Song, K.; Bai, M.; Zhou, M.; Yu, H.; Yin, B.; et al. NNMT promotes the progression of intrahepatic cholangiocarcinoma by regulating aerobic glycolysis via the EGFR-STAT3 axis. Oncogenesis 2022, 11, 39. [Google Scholar] [CrossRef]
- Hah, Y.S.; Cho, H.Y.; Jo, S.Y.; Park, Y.S.; Heo, E.P.; Yoon, T.J. Nicotinamide Nmethyltransferase Induces the Proliferation and Invasion of Squamous Cell Carcinoma Cells. Oncol. Rep. 2019, 2, 1805–1814. [Google Scholar]
- Wang, W.; Yang, C.; Wang, T.; Deng, H. Complex roles of nicotinamide N-methyltransferase in cancer progression. Cell Death Dis. 2022, 13, 267. [Google Scholar] [CrossRef]
- Li, X.-Y.; Pi, Y.-N.; Chen, Y.; Zhu, Q.; Xia, B.-R. Nicotinamide N-Methyltransferase: A Promising Biomarker and Target for Human Cancer Therapy. Front. Oncol. 2022, 12, 894744. [Google Scholar] [CrossRef]
- Lu, J.; Zhang, L.; Chen, X.; Lu, Q.; Yang, Y.; Liu, J.; Ma, X. SIRT1 counteracted the activation of STAT3 and NF-κB to repress the gastric cancer growth. Int. J. Clin. Exp. Med. 2014, 7, 5050–5058. [Google Scholar]
- Niu, G.; Wright, K.L.; Ma, Y.; Wright, G.M.; Huang, M.; Irby, R.; Briggs, J.; Karras, J.; Cress, W.D.; Pardoll, D.; et al. Role of Stat3 in regulating p53 expression and function. Mol. Cell Biol. 2005, 25, 7432–7440. [Google Scholar] [CrossRef] [Green Version]
- Pham, T.H.; Park, H.M.; Kim, J.; Hong, J.T.; Yoon, D.Y. STAT3 and p53: Dual Target for Cancer Therapy. Biomedicines 2020, 8, 637. [Google Scholar] [CrossRef] [PubMed]
- Liang, F.; Ren, C.; Wang, J.; Wang, S.; Yang, L.; Han, X.; Chen, Y.; Tong, G.; Yang, G. The crosstalk between STAT3 and p53/RAS signaling controls cancer cell metastasis and cisplatin resistance via the Slug/MAPK/PI3K/AKT-mediated regulation of EMT and autophagy. Oncogenesis 2019, 8, 59. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Singh, S.; Murillo, G.; Richner, J.; Singh, S.P.; Berleth, E.; Kumar, V.; Mehta, R.; Ramiya, V.; Parihar, A.S. A Broad-Based Characterization of a Cell-Penetrating, Single Domain Camelid Bi-Specific Antibody Monomer That Targets STAT3 and KRAS Dependent Cancers. Int. J. Mol. Sci. 2022, 23, 7565. [Google Scholar] [CrossRef] [PubMed]
- Yang, L.; Lin, S.; Xu, L.; Lin, J.; Zhao, C.; Huang, X. Novel activators and small-molecule inhibitors of STAT3 in cancer. Cytokine Growth Factor Rev. 2019, 49, 10–22. [Google Scholar] [CrossRef]
- Joshi, N.; Hajizadeh, F.; Ansari Dezfouli, E.; Zekiy, A.O.; Nabi Afjadi, M.; Mousavi, S.M.; Hojjat-Farsangi, M.; Karpisheh, V.; Mahmoodpoor, A.; Hassannia, H.; et al. Silencing STAT3 enhances sensitivity of cancer cells to doxorubicin and inhibits tumor progression. Life Sci. 2021, 275, 119369. [Google Scholar] [CrossRef]
- Chen, S.H.; Chang, J.Y. New Insights into Mechanisms of Cisplatin Resistance: From Tumor Cell to Microenvironment. Int. J. Mol. Sci. 2019, 20, 4136. [Google Scholar] [CrossRef] [Green Version]
- Morelli, A.P.; Tortelli, T.C., Jr.; Mancini, M.C.S.; Pavan, I.C.B.; Silva, L.G.S.; Severino, M.B.; Granato, D.C.; Pestana, N.F.; Ponte, L.G.S.; Peruca, G.F.; et al. STAT3 contributes to cisplatin resistance, modulating EMT markers, and the mTOR signaling in lung adenocarcinoma. Neoplasia 2021, 23, 1048–1058. [Google Scholar] [CrossRef]
- Tan, M.S.Y.; Sandanaraj, E.; Chong, Y.K.; Lim, S.W.; Koh, L.W.H.; Ng, W.H.; Tan, N.S.; Tan, P.; Ang, B.T.; Tang, C. A STAT3-based gene signature stratifies glioma patients for targeted therapy. Nat. Commun. 2019, 10, 3601. [Google Scholar] [CrossRef] [Green Version]
- Nelson, E.A.; Sharma, S.V.; Settleman, J.; Frank, D.A. A chemical biology approach to developing STAT inhibitors: Molecular strategies for accelerating clinical translation. Oncotarget 2011, 2, 518–524. [Google Scholar] [CrossRef] [Green Version]
- Remy, J.; Linder, B.; Weirauch, U.; Day, B.W.; Stringer, B.W.; Herold-Mende, C.; Aigner, A.; Krohn, K.; Kogel, D. STAT3 Enhances Sensitivity of Glioblastoma to Drug-Induced Autophagy-Dependent Cell Death. Cancers 2022, 14, 339. [Google Scholar] [CrossRef]
- Gu, H.R.; Park, S.C.; Choi, S.J.; Lee, J.C.; Kim, Y.C.; Han, C.J.; Kim, J.; Yang, K.Y.; Kim, Y.J.; Noh, G.Y.; et al. Combined treatment with silibinin and either sorafenib or gefitinib enhances their growth-inhibiting effects in hepatocellular carcinoma cells. Clin. Mol. Hepatol. 2015, 21, 49–59. [Google Scholar] [CrossRef]
- Dosch, A.R.; Singh, S.; Dai, X.; Mehra, S.; Silva, I.C.; Bianchi, A.; Srinivasan, S.; Gao, Z.; Ban, Y.; Chen, X.; et al. Targeting Tumor-Stromal IL6/STAT3 Signaling through IL1 Receptor Inhibition in Pancreatic Cancer. Mol. Cancer Ther. 2021, 20, 2280–2290. [Google Scholar] [CrossRef] [PubMed]
- Nagathihalli, N.S.; Castellanos, J.A.; VanSaun, M.N.; Dai, X.; Ambrose, M.; Guo, Q.; Xiong, Y.; Merchant, N.B. Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells. Oncotarget 2016, 7, 65982–65992. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, H.J.; Zhuang, G.; Cao, Y.; Du, P.; Kim, H.J.; Settleman, J. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell 2014, 26, 207–221. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sabet, S.; Rashidinejad, A.; Melton, L.D.; Duncan, J. Recent advances to improve curcumin oral bioavailability. Trend Food Sci. Technol. 2021, 110, 253–266. [Google Scholar] [CrossRef]
- Zhao, C.; Li, H.; Lin, H.J.; Yang, S.; Lin, J.; Liang, G. Feedback Activation of STAT3 as a Cancer Drug-Resistance Mechanism. Trends Pharmacol. Sci. 2016, 37, 47–61. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.; Shen, Y.; Wang, S.; Shen, Q.; Zhou, X. The role of STAT3 in leading the crosstalk between human cancers and the immune system. Cancer Lett. 2018, 415, 117–128. [Google Scholar] [CrossRef]
Generic Name (Brand Name) | Chemical Structure & Formula | Drug Target | Mechanism of Action | Reference Numbers |
---|---|---|---|---|
Cisplatin (Platinol) | cis-[Pt(NH3)2Cl2] | The N7 reactive center on purine nucleotide residues of DNA | Interferes with DNA replication, commonly by forming 1,2 intra- or interstrand crosslinks | [34,45,46,47,48,49,50,51,52,53,54,55] |
Docetaxel (Taxotere) | Intracellular microtubular network and Bcl-2 | Stabilizes microtubule structures to impair depolymerization and attenuation of Bcl-2 expression effects | [30,47] | |
Doxorubicin (Adriamycin) | DNA and the topoisomerase II complex of DNA | Intercalates DNA and inhibits progression of topoisomerase II to stop the replication process | [30,31,32,33,107,108,109,110,111] | |
Gemcitabine (Gemzar) | DNA nucleotides | Acts as a cytidine analog to replace nucleotides during DNA replication, causing cell arrest and apoptosis | [34,35,36,37,38,39,40,41,42,43] | |
Paclitaxel (Taxol and Others) | Tublin subunits of intracellular microtubular network | Hyperstabilizes microtubules to impair disassembly and ultimately block mitosis progression | [60,61,62,63,64,112] | |
Cyclophosphamide (Cytoxan) | C7H15Cl2N2O2P | DNA strands at guanine N-7 positions | Forms intrastrand and interstrand DNA cross-linkages | [9] |
Temozolomide (Temodar) | C6H6N6O2 | The N7 position of guanine, N3 of adenine and the O6 position of guanine | Broken down to a methyl 80-diazonium cation that methylates adenosine and guanine residues, causing DNA lesions to trigger apoptosis | [55,56,57,58,59,113,114,115] |
Afatinib (Gilotrif) | C24H25ClFN5O3 | ErbB family: EGFR (ErB1), HER2 (ErbB2), and HER4 (ErbB4) | Covalently binds to kinase domains, irreversibly preventing autophosphorylation by homo- or heterodimers | [36,59,65,66] |
Bortezomib (Velcade) | 26S proteasome | Inhibits a ubiquitin-proteasome, preventing the degradation of pro-apoptotic factors to induce cell cycle arrest | [12,16,21,24,25,27] | |
Crizotinib (Xalkori) | C21H22Cl2FN5O | ALK, HGFR, cMET, cROS, and RON | Inhibits phosphorylation in and creates an inactive protein confirmation | [67] |
Dasatinib (Sprycel) | C22H26ClN7O2S | BCR-ABL, SRC family, c-KIT, EPHA2, and PDGFRβ | Competitively binds to ATP binding site of the kinase domain | [68] |
Erlotinib (Tarceva) | Epidermal Growth Factor Receptor (EGFR) | Inhibits intracellular phosphorylation (not fully characterized) | [69,70,71,72,73] | |
Gefitinib (Iressa) | C22H24ClFN4O3 | EGFR | Competitively binds to ATP binding site of the kinase domain | [5,7,15,23,116] |
Lapatinib (Tykerb) | EGFR and Epidermal Growth Factor Receptor 2 (HER2) | Competitively binds to intracellular ATP binding site of the receptor | [10,13] | |
Vemurafenib (Zelboraf) | C23H18ClF2N3O3S | BRAF (V600E) | Competitively binds to kinase domain of mutant form of BRAF | [8,11,14,19,97] |
Imatinib (Gleevec) | BCR-ABL, ABL, CSF1R, FLT-3, c-KIT, PDGFR | Competitively binds to activate site of kinase to block phosphorylation | [17,18,26] | |
Enzalutamide (Xtandi) | Androgen Receptor (AR) | Competitively binds to the androgen receptor, preventing gene expression of AR targets | [66,67,68] | |
Flutamide (Eulexin) | Androgen Receptor | Competitively binds to the androgen receptor blocking binding and uptake of testosterones | [74,75,76] | |
Tamoxifen (Nolvadex) | C26H29NO | Estrogen Receptor (ER) | Competitively inhibits binding of estrogen to its receptor | [79,80,81,82] |
Cetuximab (Erbitux) | EGFR | Competitively inhibits the binding of epidermal growth factor (EGF) and other ligands to block the extended conformation of EGFR | [83,84,85] | |
Trastuzumab (Herceptin) | C6470H10012N1726O2013S42 | HER2 | Binds to extracellular ligand-binding domain, blocking its cleavage and inducing downregulation of the receptor | [87,88,89,90,96] |
Bevacizumab (Avastin) | Vascular endothelial growth factor (VEGF) | Binds and inactivates circulating VEGF, preventing its binding to receptor | [86] | |
Pembrolizumab (Keytruda) | PD-1 (CD279) | Binds to PD-1 on T cells to antagonize interactions with ligands, PD-L1 and PD-L2 | [100] | |
Nivolumab (Opdivo) | PD-1 | Binds to PD-1 on T cells to antagonize interactions with ligands, PD-L1 and PD-L2 | [91,92,101,103] | |
Ipilimumab (Yervoy) | CTLA-4 (CD152) | Binds CTLA-4, preventing its binding to CD28 on antigen presenting cells or T cells | [91,92,95,102,105] | |
Atezolizumab (Tecentriq) | C6446H9902N1706O1998S42 | PD-L1 (CD274) | Selectively binds to PD-L1, blocking its interaction with PD-1 or B7-1 | [6] |
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Singh, S.; Gomez, H.J.; Thakkar, S.; Singh, S.P.; Parihar, A.S. Overcoming Acquired Drug Resistance to Cancer Therapies through Targeted STAT3 Inhibition. Int. J. Mol. Sci. 2023, 24, 4722. https://doi.org/10.3390/ijms24054722
Singh S, Gomez HJ, Thakkar S, Singh SP, Parihar AS. Overcoming Acquired Drug Resistance to Cancer Therapies through Targeted STAT3 Inhibition. International Journal of Molecular Sciences. 2023; 24(5):4722. https://doi.org/10.3390/ijms24054722
Chicago/Turabian StyleSingh, Sunanda, Hector J. Gomez, Shreya Thakkar, Samara P. Singh, and Ashutosh S. Parihar. 2023. "Overcoming Acquired Drug Resistance to Cancer Therapies through Targeted STAT3 Inhibition" International Journal of Molecular Sciences 24, no. 5: 4722. https://doi.org/10.3390/ijms24054722