リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

大学・研究所にある論文を検索できる 「KRAS Inhibitor Resistance in MET-Amplified KRAS G12C Non–Small Cell Lung Cancer Induced By RAS- and Non–RAS-Mediated Cell Signaling Mechanisms」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。
リケラボ

コピーが完了しました

URLをコピーしました

論文の公開元へ論文の公開元へ
書き出し

KRAS Inhibitor Resistance in MET-Amplified KRAS G12C Non–Small Cell Lung Cancer Induced By RAS- and Non–RAS-Mediated Cell Signaling Mechanisms

鈴木 慎一郎 近畿大学

2023.01.20

概要

Purpose
Treatment with KRASG12C inhibitors such as sotorasib can produce substantial regression of tumors in some patients with non-small cell lung cancer (NSCLC). These patients require alternative treatment after acquiring resistance to the inhibitor. The mechanisms underlying this acquired resistance are unclear. The purpose of this study was to identify the mechanisms underlying acquired sotorasib resistance, and to explore potential treatments for rescuing patients with sotorasib-resistant KRASG12C NSCLC cells.
Experimental Design Clones of sotorasib-sensitive KRASG12C NSCLC H23 cells exposed to different concentrations of sotorasib were examined using whole-genomic transcriptome analysis, multiple receptor kinase phosphorylation analysis, and gene copy number evaluation.
The underlying mechanisms of resistance were investigated using immunological examination, and a treatment aimed at overcoming resistance was tested in vitro and in vivo.

Results
Unbiased screening detected subclonal evolution of MET amplification in KRASG12C NSCLC cells that had developed resistance to sotorasib in vitro. MET knockdown using siRNA restored susceptibility to sotorasib in these resistant cells. MET activation by its amplification reinforced RAS cycling from its inactive form to its active form. In addition to RAS-mediated MEK-ERK induction, MET induced AKT activation independently of RAS. Crizotinib, a MET inhibitor, restored sensitivity to sotorasib by eliminating RAS-MEK-ERK as well as AKT signaling. MET/KRASG12C dual inhibition led to tumor shrinkage in sotorasib-resistant xenograft mice.

Conclusions
MET amplification leads to the development of resistance to KRASG12C inhibitors in NSCLC. Dual blockade of MET and KRASG12C could be a treatment option for MET amplified, KRASG12C-mutated NSCLC.

論文の公開元へ

関連論文

関連論文をもっと見る

参考文献

1. Rothschild SI. Targeted therapies in non-small cell lung cancer—beyond EGFR and ALK. Cancers. 2015;7(2):930-949. DOI: 10.3390/cancers7020816, PubMed: 26018876.

2. Jiang W, Cai G, Hu PC, Wang Y. Personalized medicine in non-small cell lung cancer: a review from a pharmacogenomics perspective. Acta Pharmacol Sin B. 2018;8(4):530-538. DOI: 10.1016/j.apsb.2018.04.005, PubMed: 30109178.

3. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. DOI: 10.1056/NEJMoa1713137, PubMed: 29151359.

4. Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, et al. Alectinib versus crizotinib in untreated ALK-positive non–small-cell lung cancer. N Engl J Med. 2017;377(9):829-838. DOI: 10.1056/NEJMoa1704795, PubMed: 28586279.

5. Shaw AT, Ou SI, Bang YJ, Camidge DR, Solomon BJ, Salgia R, et al. Crizotinib in ROS1-rearranged non–small-cell lung cancer. N Engl J Med. 2014;371(21):1963-1971. DOI: 10.1056/NEJMoa1406766, PubMed: 25264305.

6. Odogwu L, Mathieu L, Blumenthal G, Larkins E, Goldberg KB, Griffin N, et al. FDA approval summary: dabrafenib and trametinib for the treatment of metastatic non‐small cell lung cancers harboring BRAF V600E mutations. Oncologist. 2018;23(6):740-745. DOI: 10.1634/theoncologist.2017-0642, PubMed: 29438093.

7. Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell. 2017;170(1):17-33. DOI: 10.1016/j.cell.2017.06.009, PubMed: 28666118.

8. Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 2014;13(11):828-851. DOI: 10.1038/nrd4389, PubMed: 25323927.

9. Biernacka A, Tsongalis PD, Peterson JD, de Abreu FB, Black CC, Gutmann EJ, et al. The potential utility of re-mining results of somatic mutation testing: KRAS status in lung adenocarcinoma. Cancer Genet. 2016;209(5):195-198. DOI: 10.1016/j.cancergen.2016.03.001, PubMed: 27068338.

10. Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract. 2009;205(12):858-862. DOI: 10.1016/j.prp.2009.07.010, PubMed: 19679400.

11. Kim D, Xue JY, Lito P. Targeting KRAS(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients. Cell. 2020;183(4):850-859. DOI: 10.1016/j.cell.2020.09.044, PubMed: 33065029.

12. Ryan MB, Corcoran RB. Therapeutic strategies to target RAS-mutant cancers. Nat Rev Clin Oncol. 2018;15(11):709-720. DOI: 10.1038/s41571-018-0105-0, PubMed: 30275515.

13. Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217-223. DOI: 10.1038/s41586-019-1694-1, PubMed: 31666701.

14. Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, et al. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 2020;10(1):54-71. DOI:10.1158/2159-8290.CD-19-1167, PubMed: 31658955.

15. Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207-1217. DOI: 10.1056/NEJMoa1917239, PubMed: 32955176.

16. Jänne PA, Rybkin II, Spira AI, Riely GJ, Papadopoulos KP, Sabari JK, et al. KRYSTAL-1: activity and safety of adagrasib (mrtx849) in advanced/metastatic non–small-cell lung cancer (NSCLC) harboring KRAS G12C mutation. Eur J Cancer. 2020;138:S1-S2. DOI:10.1016/S0959-8049(20)31076-5.

17. Fakih M, Durm GA, Govindan R, Falchook GS, Soman N, Henary HA, et al. Trial in progress: A phase Ib study of AMG 510, a specific and irreversible KRAS G12C inhibitor, in combination with other anticancer therapies in patients with advanced solid tumors harboring KRAS p.G12C mutation (CodeBreak 101). J Clin Oncol. 2020;38(15_suppl):TPS3661-TPS3661.

18. Goebel L, Müller MP, Goody RS, Rauh D. KRasG12C inhibitors in clinical trials: a short historical perspective. RSC Med Chem. 2020;11(7):760-770. DOI: 10.1039/D0MD00096E, PubMed: 33479673.

19. Mechanisms of KRAS inhibitor resistance revealed. Cancer Discov. 2021. DOI:10.1158/2159-8290.CD-NB2021-0335, PubMed: 33853790.

20. Scheffler M, Ihle MA, Hein R, Merkelbach-Bruse S, Scheel AH, Siemanowski J, et al. K-ras mutation subtypes in NSCLC and associated co-occuring mutations in other oncogenic pathways. J Thorac Oncol. 2019;14(4):606-616. DOI: 10.1016/j.jtho.2018.12.013, PubMed: 30605727.

21. Pasquini G, Giaccone G. C-MET inhibitors for advanced non-small cell lung cancer. Expert Opin Investig Drugs. 2018;27(4):363-375. DOI: 10.1080/13543784.2018.1462336, PubMed: 29621416.

22. Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005;225(1):1-26. DOI: 10.1016/j.canlet.2004.09.044, PubMed: 15922853.

23. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316(5827):1039-1043. DOI: 10.1126/science.1141478, PubMed: 17463250.

24. Schildhaus HU, Schultheis AM, Rüschoff J, Binot E, Merkelbach-Bruse S, Fassunke J, et al. MET amplification status in therapy-naive adeno- and squamous cell carcinomas of the lung. Clin Cancer Res. 2015;21(4):907-915. DOI: 10.1158/1078-0432.CCR-14-0450, PubMed: 25492085.

25. Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 2011;3(99):99ra86-99ra86. DOI: 10.1126/scitranslmed.3002442, PubMed: 21900593.

26. Wolf J, Seto T, Han JY, Reguart N, Garon EB, Groen HJM, et al. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. N Engl J Med. 2020;383(10):944-957. DOI: 10.1056/NEJMoa2002787, PubMed: 32877583.

27. Hofmann MH, Gmachl M, Ramharter J, Savarese F, Gerlach D, Marszalek JR, et al. BI-3406, a potent and selective SOS1–KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition. Cancer Discov. 2020;11(1):142-157. DOI: 10.1158/2159-8290.CD-20-0142, PubMed: 32816843.

28. Nichols RJ, Haderk F, Stahlhut C, Schulze CJ, Hemmati G, Wildes D, et al. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat Cell Biol. 2018;20(9):1064-1073. DOI: 10.1038/s41556-018-0169-1, PubMed: 30104724.

29. Lito P, Solomon M, Li LS, Hansen R, Rosen N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science. 2016;351(6273):604-608. DOI: 10.1126/science.aad6204, PubMed: 26841430.

30. Ryan MB, Fece de la Cruz F, Phat S, Myers DT, Wong E, Shahzade HA, et al. Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition. Clin Cancer Res. 2020;26(7):1633-1643. DOI: 10.1158/1078-0432.CCR-19-3523, PubMed: 31776128.

31. Misale S, Fatherree JP, Cortez E, Li C, Bilton S, Timonina D, et al. KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition. Clin Cancer Res. 2019;25(2):796-807. DOI: 10.1158/1078-0432.CCR-18-0368, PubMed: 30327306.

32. Adachi Y, Ito K, Hayashi Y, Kimura R, Tan TZ, Yamaguchi R, et al. Epithelial-to-mesenchymal transition is a cause of both intrinsic and acquired resistance to KRAS G12C inhibitor in KRAS G12C–mutant non–small cell lung cancer. Clin Cancer Res. 2020;26(22):5962-5973. DOI: 10.1158/1078-0432.CCR-20-2077, PubMed: 32900796.

33. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med. 2008;14(12):1351-1356. DOI: 10.1038/nm.1890, PubMed: 19029981.

34. Shimizu T, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, Smith LS, et al. The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer. Clin Cancer Res. 2012;18(8):2316-2325. DOI: 10.1158/1078-0432.CCR-11-2381, PubMed: 22261800.

35. Riedel R, Michels S, Heydt C, Siemanowski J, Kobe C, Bunck A, et al. Acquired KRAS mutation and loss of low-level MET amplification after durable response to crizotinib in a patient with lung adenocarcinoma. Lung Cancer. 2019;133:20-22. DOI: 10.1016/j.lungcan.2019.05.006, PubMed: 31200822.

36. Hellman A, Zlotorynski E, Scherer SW, Cheung J, Vincent JB, Smith DI, et al. A role for common fragile site induction in amplification of human oncogenes. Cancer Cell. 2002;1(1):89-97. DOI: 10.1016/s1535-6108(02)00017-x, PubMed: 12086891.

37. Dagogo-Jack I, Yoda S, Lennerz JK, Langenbucher A, Lin JJ, Rooney MM, et al. MET alterations are a recurring and actionable resistance mechanism in ALK-positive lung cancer. Clin Cancer Res. 2020;26(11):2535-2545. DOI: 10.1158/1078-0432.CCR-19-3906, PubMed: 32086345.

38. Rosen EY, Johnson ML, Clifford SE, Somwar R, Kherani JF, Son J, et al. Overcoming MET-dependent resistance to selective RET inhibition in patients with RET fusion–positive lung cancer by combining selpercatinib with crizotinib. Clin Cancer Res. 2021;27(1):34-42. DOI: 10.1158/1078-0432.CCR-20-2278, PubMed: 33082208.

39. Wu YL, Cheng Y, Zhou J, Lu S, Zhang Y, Zhao J, et al. Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (Insight study): an open-label, phase 1b/2, multicentre, randomised trial. Lancet Respir Med. 2020;8(11):1132-1143. DOI: 10.1016/S2213-2600(20)30154-5, PubMed: 32479794.

40. Gautschi O, Menon R, Bertrand M, Murer C, Diebold J. Capmatinib and osimertinib combination therapy for EGFR-mutant lung adenocarcinoma. J Thorac Oncol. 2020;15(1):e13-e15. DOI: 10.1016/j.jtho.2019.07.027, PubMed: 31864554.

41. Sequist LV, Han JY, Ahn MJ, Cho BC, Yu H, Kim SW, et al. Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study. Lancet Oncol. 2020;21(3):373-386. DOI: 10.1016/S1470-2045(19)30785-5, PubMed: 32027846.

参考文献をもっと見る

全国の大学の
卒論・修論・学位論文
を
一発検索！

この論文の関連論文を見る