Abstract
Background
Despite remarkable activity in epidermal growth factor receptor (EGFR)-mutant lung cancer patients, the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) is limited by the emergence of acquired resistance, which is mostly caused by a secondary T790M mutation. Fortunately, newly developed, mutant-selective EGFR-TKIs against T790M have been proven as an effective therapeutic approach although only osimertinib has received the FDA approval until now.
Objective
To determine the in vitro and in vivo efficacy of a new EGFR TKI, OBX1-012 in cells with mutant EGFR.
Methods
Effects of OBX1-012 on cellular viability and EGFR-related signaling were determined in EGFR-mutant non-small cell lung cancer (NSCLC) cells, including cells harboring T790M mutations. In addition, in vivo efficacy of OBX1-012 was evaluated in xenograft models.
Results
We report the discovery and preclinical assessment of another novel, mutant-selective EGFR-TKI, OBX1-012. Compared with other mutant-selective EGFR-TKIs such as olumitinib and osimertinib, it showed similar potency and selectivity for mutant EGFR. OBX1-012 treatment was highly effective against human EGFR-mutant lung cancer models with or without EGFR T790M, not only in vitro but also in vivo. However, OBX1-012 like other EGFR-TKIs failed to exhibit efficacy for the exon 20 insertion mutation or C797S mutation, which was generated by site-directed mutagenesis and stable transfection of Ba/F3 cells.
Conclusions
These results identify OBX1-012 as a highly effective, mutant-selective EGFR-TKI for the treatment of T790M-mediated resistance in NSCLC.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. https://doi.org/10.3322/caac.20107.
Ji H, Li D, Chen L, Shimamura T, Kobayashi S, McNamara K, et al. The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell. 2006;9(6):485–95. https://doi.org/10.1016/j.ccr.2006.04.022.
Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97(5):339–46. https://doi.org/10.1093/jnci/dji055.
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57. https://doi.org/10.1056/NEJMoa0810699.
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, 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(3):239–46. https://doi.org/10.1016/S1470-2045(11)70393-X.
Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327–34. https://doi.org/10.1200/JCO.2012.44.2806.
Chang YS, Choi CM, Lee JC. Mechanisms of epidermal growth factor receptor tyrosine kinase inhibitor resistance and strategies to overcome resistance in lung adenocarcinoma. Tuberc Respir Dis (Seoul). 2016;79(4):248–56. https://doi.org/10.4046/trd.2016.79.4.248.
Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352(8):786–92. https://doi.org/10.1056/NEJMoa044238.
Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19(8):2240–7. https://doi.org/10.1158/1078-0432.CCR-12-2246.
Politi K, Ayeni D, Lynch T. The next wave of EGFR tyrosine kinase inhibitors enter the clinic. Cancer Cell. 2015;27(6):751–3. https://doi.org/10.1016/j.ccell.2015.05.012.
Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689–99. https://doi.org/10.1056/NEJMoa1411817.
Sequist LV, Rolfe L, Allen AR. Rociletinib in EGFR-mutated non-small-cell lung Cancer. N Engl J Med. 2015;373(6):578–9. https://doi.org/10.1056/NEJMc1506831.
Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629–40. https://doi.org/10.1056/NEJMoa1612674.
Ballard P, Yates JW, Yang Z, Kim DW, Yang JC, Cantarini M, et al. Preclinical comparison of Osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res. 2016;22(20):5130–40. https://doi.org/10.1158/1078-0432.CCR-16-0399.
Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113–25. https://doi.org/10.1056/NEJMoa1713137.
Kim ES. Olmutinib: first global approval. Drugs. 2016;76(11):1153–7. https://doi.org/10.1007/s40265-016-0606-z.
Rho JK, Choi YJ, Jeon BS, Choi SJ, Cheon GJ, Woo SK, et al. Combined treatment with silibinin and epidermal growth factor receptor tyrosine kinase inhibitors overcomes drug resistance caused by T790M mutation. Mol Cancer Ther. 2010;9(12):3233–43. https://doi.org/10.1158/1535-7163.MCT-10-0625.
Rho JK, Choi YJ, Lee JK, Ryoo BY, Na II, Yang SH, et al. The role of MET activation in determining the sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors. Mol Cancer Res. 2009;7(10):1736–43. https://doi.org/10.1158/1541-7786.MCR-08-0504.
Rho JK, Lee IY, Choi YJ, Choi CM, Hur JY, Koh JS, et al. Superior efficacy and selectivity of novel small-molecule kinase inhibitors of T790M-mutant EGFR in preclinical models of lung cancer. Cancer Res. 2017;77(5):1200–11. https://doi.org/10.1158/0008-5472.CAN-16-2432.
Greulich H, Chen TH, Feng W, Janne PA, Alvarez JV, Zappaterra M, et al. Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med. 2005;2(11):e313. https://doi.org/10.1371/journal.pmed.0020313.
Jia Y, Yun CH, Park E, Ercan D, Manuia M, Juarez J, et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 2016;534(7605):129–32. https://doi.org/10.1038/nature17960.
Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015;21(6):560–2. https://doi.org/10.1038/nm.3854.
Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol. 2012;13(1):e23–31. https://doi.org/10.1016/S1470-2045(11)70129-2.
Nosaki K, Satouchi M, Kurata T, Yoshida T, Okamoto I, Katakami N, et al. Re-biopsy status among non-small cell lung cancer patients in Japan: a retrospective study. Lung Cancer. 2016;101:1–8. https://doi.org/10.1016/j.lungcan.2016.07.007.
Takeda M, Okamoto I, Nakagawa K. Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. Lung Cancer. 2015;88(1):74–9. https://doi.org/10.1016/j.lungcan.2015.01.026.
Arulananda S, Do H, Musafer A, Mitchell P, Dobrovic A, John T. Combination osimertinib and gefitinib in C797S and T790M EGFR-mutated non-small cell lung Cancer. J Thorac Oncol. 2017;12(11):1728–32. https://doi.org/10.1016/j.jtho.2017.08.006.
Ramalingam SS, Yang JC, Lee CK, Kurata T, Kim DW, John T, et al. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J Clin Oncol. 2017; https://doi.org/10.1200/JCO.2017.74.7576.
Acknowledgments
We thank the core facilities of Laboratory of Animal Research at the ConveRgence mEDIcine research center (CREDIT), Asan Medical Center for the use of their shared equipment, services and expertise. The authors would like to thank Enago (http://www.enago.co.kr) for the English language review.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Funding
This study was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant HI15C0516 and HI15C0972) and a grant of Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2017R1A6A3A01002444).
Conflict of Interest
Dong Ha Kim, Yun Jung Choi, Seon Ye Kim, Jung-Eun Lee, Ki Jung Sung, Young Hoon Sung, Woo Sung Kim, Sung-Eun Kim, Hyung Chul Ryu, Jae Sun Kim, Lu Guangying, Chang-Min Choi, Jin Kyung Rho, and Jae Cheol Lee declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.
Electronic supplementary material
ESM 1
(PDF 222 kb)
Rights and permissions
About this article
Cite this article
Kim, D.H., Choi, Y.J., Kim, S.Y. et al. Discovery of a Potent and Mutant-Selective EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Lung Cancer. Targ Oncol 13, 389–398 (2018). https://doi.org/10.1007/s11523-018-0568-z
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11523-018-0568-z