CRISPR Screening Identifies Mechanisms of Resistance to KRASG12C and SHP2 Inhibitor Combinations in Non-Small Cell Lung Cancer

Overview

Journal Cancer Res

Specialty Oncology

Date 2023 Nov 7

PMID 37934115

Authors

Anirudh Prahallad

Andreas Weiss

Hans Voshol

Grainne Kerr

Kathleen Sprouffske

Tina Yuan

David Ruddy

Morgane Meistertzheim

Malika Kazic-Legueux

Tina Kottarathil

Michelle Piquet

Yichen Cao

Laetitia Martinuzzi-Duboc

Alexandra Buhles

Flavia Adler

Salvatore Mannino

Luca Tordella

Laurent Sansregret

Sauveur-Michel Maira

Diana Graus Porta

Carmine Fedele

Saskia M Brachmann

Affiliations

Soon will be listed here.

Abstract

Significance: Identification of resistance mechanisms to KRASG12C/SHP2 coinhibition highlights the need for additional combination therapies for lung cancer beyond on-pathway combinations and offers the basis for development of more effective combination approaches. See related commentary by Johnson and Haigis, p. 4005.

Citing Articles

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References

Donovan S, Shannon K, Bollag G . GTPase activating proteins: critical regulators of intracellular signaling. Biochim Biophys Acta. 2002; 1602(1):23-45. DOI: 10.1016/s0304-419x(01)00041-5. View

Zanconato F, Forcato M, Battilana G, Azzolin L, Quaranta E, Bodega B . Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat Cell Biol. 2015; 17(9):1218-27. PMC: 6186417. DOI: 10.1038/ncb3216. View

Wang T, Maierhofer C, Speicher M, Lengauer C, Vogelstein B, Kinzler K . Digital karyotyping. Proc Natl Acad Sci U S A. 2002; 99(25):16156-61. PMC: 138581. DOI: 10.1073/pnas.202610899. View

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

Krall E, Wang B, Munoz D, Ilic N, Raghavan S, Niederst M . KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. Elife. 2017; 6. PMC: 5305212. DOI: 10.7554/eLife.18970. View

Molina J, Yang P, Cassivi S, Schild S, Adjei A . Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008; 83(5):584-94. PMC: 2718421. DOI: 10.4065/83.5.584. View

Molina-Arcas M, Moore C, Rana S, van Maldegem F, Mugarza E, Romero-Clavijo P . Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci Transl Med. 2019; 11(510). PMC: 6764843. DOI: 10.1126/scitranslmed.aaw7999. View

Whittaker S, Theurillat J, Van Allen E, Wagle N, Hsiao J, Cowley G . A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition. Cancer Discov. 2013; 3(3):350-62. PMC: 3606893. DOI: 10.1158/2159-8290.CD-12-0470. View

Yaeger R, Mezzadra R, Sinopoli J, Bian Y, Marasco M, Kaplun E . Molecular Characterization of Acquired Resistance to KRASG12C-EGFR Inhibition in Colorectal Cancer. Cancer Discov. 2022; 13(1):41-55. PMC: 9827113. DOI: 10.1158/2159-8290.CD-22-0405. View

10.

Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin A, Kim S . The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012; 483(7391):603-7. PMC: 3320027. DOI: 10.1038/nature11003. View

11.

Bennett A, Hausdorff S, OReilly A, Freeman R, Neel B . Multiple requirements for SHPTP2 in epidermal growth factor-mediated cell cycle progression. Mol Cell Biol. 1996; 16(3):1189-202. PMC: 231101. DOI: 10.1128/MCB.16.3.1189. View

12.

Hunter J, Manandhar A, Carrasco M, Gurbani D, Gondi S, Westover K . Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations. Mol Cancer Res. 2015; 13(9):1325-35. DOI: 10.1158/1541-7786.MCR-15-0203. View

13.

Castellano E, Sheridan C, Zaw Thin M, Nye E, Spencer-Dene B, Diefenbacher M . Requirement for interaction of PI3-kinase p110α with RAS in lung tumor maintenance. Cancer Cell. 2013; 24(5):617-30. PMC: 3826036. DOI: 10.1016/j.ccr.2013.09.012. View

14.

Ornitz D, Itoh N . The Fibroblast Growth Factor signaling pathway. Wiley Interdiscip Rev Dev Biol. 2015; 4(3):215-66. PMC: 4393358. DOI: 10.1002/wdev.176. View

15.

Negrao M, Araujo H, Lamberti G, Cooper A, Akhave N, Zhou T . Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC. Cancer Discov. 2023; 13(7):1556-1571. PMC: 11024958. DOI: 10.1158/2159-8290.CD-22-1420. View

16.

Rago F, DiMare M, Elliott G, Ruddy D, Sovath S, Kerr G . Degron mediated BRM/SMARCA2 depletion uncovers novel combination partners for treatment of BRG1/SMARCA4-mutant cancers. Biochem Biophys Res Commun. 2018; 508(1):109-116. DOI: 10.1016/j.bbrc.2018.09.009. View

17.

Kapoor A, Yao W, Ying H, Hua S, Liewen A, Wang Q . Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell. 2014; 158(1):185-197. PMC: 4109295. DOI: 10.1016/j.cell.2014.06.003. View

18.

Malumbres M, Barbacid M . RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003; 3(6):459-65. DOI: 10.1038/nrc1097. View

19.

Misale S, Fatherree J, Cortez E, Li C, Bilton S, Timonina D . KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition. Clin Cancer Res. 2018; 25(2):796-807. DOI: 10.1158/1078-0432.CCR-18-0368. View

20.

Guagnano V, Furet P, Spanka C, Bordas V, Le Douget M, Stamm C . Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem. 2011; 54(20):7066-83. DOI: 10.1021/jm2006222. View