DNA Polymerase Alpha Subunit B Is a Binding Protein for Erlotinib Resistance in Non-Small Cell Lung Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Selection of an Erlotinib-Resistant Cell Line
2.2. DARTS LC-MS/MS SWATH Analysis for Protein Target Identification
2.3. Identification of New Erlotinib Binding Proteins
2.4. POLA2: A Novel Erlotinib Resistance Marker
2.5. Pola2 Is a Potential Erlotinib-Resistant Biomarker
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Cell Culture
4.3. Proliferation Assay
4.4. DARTS Assay
4.5. In Silico Docking Study
4.6. Immunoblot Analysis
4.7. RNA Interference and Overexpression Analysis
4.8. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2013. CA Cancer J. Clin. 2013, 63, 11–30. [Google Scholar] [CrossRef] [Green Version]
- Shah, R.; Lester, J.F. Tyrosine Kinase Inhibitors for the Treatment of EGFR Mutation-Positive Non-Small-Cell Lung Cancer: A Clash of the Generations. Clin. Lung Cancer 2020, 21, e216–e228. [Google Scholar] [CrossRef]
- Ettinger, D.S.; Wood, D.E.; Aggarwal, C.; Aisner, D.L.; Akerley, W.; Bauman, J.R.; Bharat, A.; Bruno, D.S.; Chang, J.Y.; Chirieac, L.R.; et al. NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 1.2020. J. Natl. Compr. Canc. Netw. 2019, 17, 1464–1472. [Google Scholar] [CrossRef] [Green Version]
- Al Olayan, A.; Al Hussaini, H.; Jazieh, A.R. The roles of epidermal growth factor receptor (EGFR) inhibitors in the management of lung cancer. J. Infect. Public Health 2012, 5 (Suppl. 1), S50–S60. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, C.K.; Brown, C.; Gralla, R.J.; Hirsh, V.; Thongprasert, S.; Tsai, C.M.; Tan, E.H.; Ho, J.C.; Chu da, T.; Zaatar, A.; et al. Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: A meta-analysis. J. Natl. Cancer Inst. 2013, 105, 595–605. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, J.K.; Hahn, S.; Kim, D.W.; Suh, K.J.; Keam, B.; Kim, T.M.; Lee, S.H.; Heo, D.S. Epidermal growth factor receptor tyrosine kinase inhibitors vs conventional chemotherapy in non-small cell lung cancer harboring wild-type epidermal growth factor receptor: A meta-analysis. JAMA 2014, 311, 1430–1437. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- U.S. Food and Drug Administration. Available online: http://www.accessdata.fda.gov/drugsatfda_docs/label/ (accessed on 18 February 2020).
- Sequist, L.V. First-generation epidermal growth factor receptor tyrosine kinase inhibitors in EGFR mutation: Positive non-small cell lung cancer patients. J. Thorac. Oncol. 2008, 3, S143–S145. [Google Scholar] [CrossRef] [Green Version]
- Rosell, R.; Carcereny, E.; Gervais, R.; Vergnenegre, A.; Massuti, B.; Felip, E.; Palmero, R.; Garcia-Gomez, R.; Pallares, C.; Sanchez, J.M.; et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012, 13, 239–246. [Google Scholar] [CrossRef]
- Zhou, C.; Wu, Y.-L.; Chen, G.; Feng, J.; Liu, X.-Q.; Wang, C.; Zhang, S.; Wang, J.; Zhou, S.; Ren, S.; et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011, 12, 735–742. [Google Scholar] [CrossRef]
- Yuan, M.; Huang, L.L.; Chen, J.H.; Wu, J.; Xu, Q. The emerging treatment landscape of targeted therapy in non-small-cell lung cancer. Signal Transduct. Target. Ther. 2019, 4, 61. [Google Scholar] [CrossRef] [Green Version]
- Neumair, P.; Joos, L.; Warschkow, R.; Dutly, A.; Ess, S.; Hitz, F.; Fruh, M.; Brutsche, M.; Baty, F.; Krahenbuhl, S.; et al. Erlotinib has comparable clinical efficacy to chemotherapy in pretreated patients with advanced non-small cell lung cancer (NSCLC): A propensity-adjusted, outcomes research-based study. Lung Cancer 2016, 100, 38–44. [Google Scholar] [CrossRef] [PubMed]
- Chen, Y.; Tang, W.Y.; Tong, X.; Ji, H. Pathological transition as the arising mechanism for drug resistance in lung cancer. Cancer Commun. 2019, 39, 53. [Google Scholar] [CrossRef] [Green Version]
- Beltran, H.; Hruszkewycz, A.; Scher, H.I.; Hildesheim, J.; Isaacs, J.; Yu, E.Y.; Kelly, K.; Lin, D.; Dicker, A.; Arnold, J.; et al. The Role of Lineage Plasticity in Prostate Cancer Therapy Resistance. Clin. Cancer Res. 2019, 25, 6916–6924. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hu, J.; Han, B.; Huang, J. Morphologic Spectrum of Neuroendocrine Tumors of the Prostate: An Updated Review. Arch. Pathol. Lab. Med. 2020, 144, 320–325. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Riely, G.J.; Pao, W.; Pham, D.; Li, A.R.; Rizvi, N.; Venkatraman, E.S.; Zakowski, M.F.; Kris, M.G.; Ladanyi, M.; Miller, V.A. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin. Cancer Res. 2006, 12, 839–844. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jackman, D.M.; Yeap, B.Y.; Sequist, L.V.; Lindeman, N.; Holmes, A.J.; Joshi, V.A.; Bell, D.W.; Huberman, M.S.; Halmos, B.; Rabin, M.S.; et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin. Cancer Res. 2006, 12, 3908–3914. [Google Scholar] [CrossRef] [Green Version]
- Walter, A.O.; Sjin, R.T.; Haringsma, H.J.; Ohashi, K.; Sun, J.; Lee, K.; Dubrovskiy, A.; Labenski, M.; Zhu, Z.; Wang, Z.; et al. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov. 2013, 3, 1404–1415. [Google Scholar] [CrossRef] [Green Version]
- Sequist, L.V.; Waltman, B.A.; Dias-Santagata, D.; Digumarthy, S.; Turke, A.B.; Fidias, P.; Bergethon, K.; Shaw, A.T.; Gettinger, S.; Cosper, A.K.; et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 2011, 3, 75ra26. [Google Scholar] [CrossRef] [Green Version]
- Sharma, S.V.; Bell, D.W.; Settleman, J.; Haber, D.A. Epidermal growth factor receptor mutations in lung cancer. Nat. Rev. Cancer 2007, 7, 169–181. [Google Scholar] [CrossRef]
- Bean, J.; Brennan, C.; Shih, J.Y.; Riely, G.; Viale, A.; Wang, L.; Chitale, D.; Motoi, N.; Szoke, J.; Broderick, S.; et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc. Natl. Acad. Sci. USA 2007, 104, 20932–20937. [Google Scholar] [CrossRef] [Green Version]
- Jakobsen, K.R.; Demuth, C.; Sorensen, B.S.; Nielsen, A.L. The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Transl. Lung Cancer Res. 2016, 5, 172–182. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sos, M.L.; Koker, M.; Weir, B.A.; Heynck, S.; Rabinovsky, R.; Zander, T.; Seeger, J.M.; Weiss, J.; Fischer, F.; Frommolt, P.; et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res. 2009, 69, 3256–3261. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Blakely, C.M.; Bivona, T.G. Resiliency of lung cancers to EGFR inhibitor treatment unveiled, offering opportunities to divide and conquer EGFR inhibitor resistance. Cancer Discov. 2012, 2, 872–875. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ramirez, M.; Rajaram, S.; Steininger, R.J.; Osipchuk, D.; Roth, M.A.; Morinishi, L.S.; Evans, L.; Ji, W.; Hsu, C.H.; Thurley, K.; et al. Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells. Nat. Commun. 2016, 7, 10690. [Google Scholar] [CrossRef]
- Mphahlele, M.J.; Mmonwa, M.M.; Aro, A.; McGaw, L.J.; Choong, Y.S. Synthesis, Biological Evaluation and Molecular Docking of Novel Indole-Aminoquinazoline Hybrids for Anticancer Properties. Int. J. Mol. Sci 2018, 19, 2232. [Google Scholar] [CrossRef] [Green Version]
- Sorensen, B.S.; Wu, L.; Wei, W.; Tsai, J.; Weber, B.; Nexo, E.; Meldgaard, P. Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and resistance mutations in the plasma DNA of patients with advanced non-small cell lung cancer during treatment with erlotinib. Cancer 2014, 120, 3896–3901. [Google Scholar] [CrossRef] [Green Version]
- Foiani, M.; Marini, F.; Gamba, D.; Lucchini, G.; Plevani, P. The B subunit of the DNA polymerase alpha-primase complex in Saccharomyces cerevisiae executes an essential function at the initial stage of DNA replication. Mol. Cell. Biol. 1994, 14, 923–933. [Google Scholar] [CrossRef] [Green Version]
- Petrilli, W.L.; Adam, G.C.; Erdmann, R.S.; Abeywickrema, P.; Agnani, V.; Ai, X.; Baysarowich, J.; Byrne, N.; Caldwell, J.P.; Chang, W.; et al. From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9. Cell Chem. Biol. 2020, 27, 32–40.e3. [Google Scholar] [CrossRef]
- Chang, J.; Kim, Y.; Kwon, H.J. Advances in identification and validation of protein targets of natural products without chemical modification. Nat. Prod. Rep. 2016, 33, 719–730. [Google Scholar] [CrossRef]
- Jafari, R.; Almqvist, H.; Axelsson, H.; Ignatushchenko, M.; Lundback, T.; Nordlund, P.; Martinez Molina, D. The cellular thermal shift assay for evaluating drug target interactions in cells. Nat. Protoc. 2014, 9, 2100–2122. [Google Scholar] [CrossRef]
- Ohashi, K.; Sequist, L.V.; Arcila, M.E.; Lovly, C.M.; Chen, X.; Rudin, C.M.; Moran, T.; Camidge, D.R.; Vnencak-Jones, C.L.; Berry, L.; et al. Characteristics of lung cancers harboring NRAS mutations. Clin. Cancer Res. 2013, 19, 2584–2591. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pavlov, Y.I.; Frahm, C.; Nick McElhinny, S.A.; Niimi, A.; Suzuki, M.; Kunkel, T.A. Evidence that errors made by DNA polymerase alpha are corrected by DNA polymerase delta. Curr. Biol. 2006, 16, 202–207. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Moldovan, G.L.; Pfander, B.; Jentsch, S. PCNA, the maestro of the replication fork. Cell 2007, 129, 665–679. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bivona, T.G.; Hieronymus, H.; Parker, J.; Chang, K.; Taron, M.; Rosell, R.; Moonsamy, P.; Dahlman, K.; Miller, V.A.; Costa, C.; et al. FAS and NF-kappaB signalling modulate dependence of lung cancers on mutant EGFR. Nature 2011, 471, 523–526. [Google Scholar] [CrossRef] [Green Version]
- Dong, J.K.; Lei, H.M.; Liang, Q.; Tang, Y.B.; Zhou, Y.; Wang, Y.; Zhang, S.; Li, W.B.; Tong, Y.; Zhuang, G.; et al. Overcoming erlotinib resistance in EGFR mutation-positive lung adenocarcinomas through repression of phosphoglycerate dehydrogenase. Theranostics 2018, 8, 1808–1823. [Google Scholar] [CrossRef] [Green Version]
- Jakobsen, K.R.; Demuth, C.; Madsen, A.T.; Hussmann, D.; Vad-Nielsen, J.; Nielsen, A.L.; Sorensen, B.S. MET amplification and epithelial-to-mesenchymal transition exist as parallel resistance mechanisms in erlotinib-resistant, EGFR-mutated, NSCLC HCC827 cells. Oncogenesis 2017, 6, e307. [Google Scholar] [CrossRef]
- Qiao, H.; Zhao, D.; Shi, H.; Ren, K.; Li, J.; Li, E. Novel quinazoline derivatives exhibit antitumor activity by inhibiting JAK2/STAT3. Oncol. Rep. 2015, 34, 1875–1882. [Google Scholar] [CrossRef] [Green Version]
- Hwang, H.-Y.; Kim, T.Y.; Szász, M.A.; Dome, B.; Malm, J.; Marko-Varga, G.; Kwon, H.J. Profiling the Protein Targets of Unmodified Bio-Active Molecules with Drug Affinity Responsive Target Stability and Liquid Chromatography/Tandem Mass Spectrometry. Proteomics 2020, 20, e1900325. [Google Scholar] [CrossRef]
- Nyberg, F.; Ogiwara, A.; Harbron, C.G.; Kawakami, T.; Nagasaka, K.; Takami, S.; Wada, K.; Tu, H.K.; Otsuji, M.; Kyono, Y.; et al. Proteomic biomarkers for acute interstitial lung disease in gefitinib-treated Japanese lung cancer patients. PLoS ONE 2011, 6, e22062. [Google Scholar] [CrossRef]
- Marko-Varga, G.; Ogiwara, A.; Nishimura, T.; Kawamura, T.; Fujii, K.; Kawakami, T.; Kyono, Y.; Tu, H.-k.; Anyoji, H.; Kanazawa, M.; et al. Personalized Medicine and Proteomics: Lessons from Non-Small Cell Lung Cancer. J. Proteome Res. 2007, 6, 2925–2935. [Google Scholar] [CrossRef]
- Amato, K.R.; Wang, S.; Tan, L.; Hastings, A.K.; Song, W.; Lovly, C.M.; Meador, C.B.; Ye, F.; Lu, P.; Balko, J.M.; et al. EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer. Cancer Res. 2016, 76, 305–318. [Google Scholar] [CrossRef] [PubMed] [Green Version]
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Kim, T.Y.; Ji, E.S.; Lee, J.Y.; Kim, J.Y.; Yoo, J.S.; Szasz, A.M.; Dome, B.; Marko-Varga, G.; Kwon, H.J. DNA Polymerase Alpha Subunit B Is a Binding Protein for Erlotinib Resistance in Non-Small Cell Lung Cancer. Cancers 2020, 12, 2613. https://doi.org/10.3390/cancers12092613
Kim TY, Ji ES, Lee JY, Kim JY, Yoo JS, Szasz AM, Dome B, Marko-Varga G, Kwon HJ. DNA Polymerase Alpha Subunit B Is a Binding Protein for Erlotinib Resistance in Non-Small Cell Lung Cancer. Cancers. 2020; 12(9):2613. https://doi.org/10.3390/cancers12092613
Chicago/Turabian StyleKim, Tae Young, Eun Sun Ji, Ju Yeon Lee, Jin Young Kim, Jong Shin Yoo, A. Marcell Szasz, Balazs Dome, Gyorgy Marko-Varga, and Ho Jeong Kwon. 2020. "DNA Polymerase Alpha Subunit B Is a Binding Protein for Erlotinib Resistance in Non-Small Cell Lung Cancer" Cancers 12, no. 9: 2613. https://doi.org/10.3390/cancers12092613