Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC

Negrão, Marcelo V.; Araújo, Haniel A.; Lamberti, Giuseppe; Cooper, Alissa J.; Akhave, Neal S.; Zhou, Teng; Delasos, Lukas; Hicks, J. Kevin; Aldea, Mihaela; Minuti, Gabriele; Hines, Jacobi; Aredo, Jacqueline V.; Dennis, Michael J.; Chakrabarti, Turja; Scott, Susan C.; Bironzo, Paolo; Scheffler, Matthias; Christopoulos, Petros; Stenzinger, Albrecht; Riess, Jonathan W.; Kim, So Yeon; Goldberg, Sarah B.; Li, Mingjia; Wang, Qi; Qing, Yun; Ni, Ying; Truong, Minh; Lee, Richard; Ricciuti, Biagio; Alessi, Joao V.; Wang, Jing; Resuli, Blerina; Landi, Lorenza; Tseng, Shu-Chi; Nishino, Mizuki; Digumarthy, Subba R.; Rinsurongkawong, Waree; Rinsurongkawong, Vadeerat; Vaporciyan, Ara A.; Blumenschein, George R.; Zhang, Jianjun; Owen, Dwight H.; Blakely, Collin M.; Mountzios, Giannis; Shu, Catherine A.; Bestvina, Christine M.; Garassino, Marina Chiara; Marrone, Kristen A.; Gray, Jhanelle E.; Patel, Sandip Pravin; Cummings, Amy L.; Wakelee, Heather A.; Wolf, Juergen; Scagliotti, Giorgio V.; Cappuzzo, Federico; Barlési, Fabrice; Patil, Pradnya D.; Drusbosky, Leylah; Gibbons, Don L.; Meric‐Bernstam, Funda; Lee, J. Jack; Heymach, John V.; Hong, David S.; Heist, Rebecca S.; Awad, Mark M.; Skoulidis, Ferdinandos

doi:10.1158/2159-8290.cd-22-1420

articleCancer DiscoveryApr 17, 2023GREEN OA

Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC

MVMarcelo V. Negrão HAHaniel A. Araújo GLGiuseppe Lamberti AJAlissa J. Cooper NSNeal S. Akhave

The University of Texas MD Anderson Cancer Center · Dana-Farber Cancer Institute · +28 more institutions

PubMed

Indexed incrossrefpubmed

Abstract

Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated…

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