Open AccessA saturation mutagenesis screen uncovers resistant and sensitizing secondary KRAS mutations to clinical KRAS G12C inhibitors
Author(s) -
Siyu Feng,
Marinella G Callow,
JeanPhilippe Fortin,
Zia Khan,
David A. Bray,
Mike Costa,
Zhiyu Shi,
Weiru Wang,
Marie Evangelista
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2120512119
Subject(s) - kras , biology , saturated mutagenesis , pi3k/akt/mtor pathway , mutant , mutation , protein kinase b , cancer research , mutagenesis , genetics , signal transduction , gene
Significance KRASG12C inhibitors have demonstrated promising efficacy in non–small-cell lung cancer patients harboring the KRASG12C mutation. However, the mechanism of resistance remains to be fully understood. To understand the consequences of single amino acid changes within KRASG12C , we conducted a saturation mutagenesis screen of the KRASG12C protein and assessed the mutational impact on drug sensitivity. Not only did our screen reveal resistant hits that were identified from patients’ samples (V8L, C12F, R68S, H95D, H95R, and Y96C), but we also discovered variants that sensitize the inhibition. Furthermore, we examined the human genetics databases and identified germline or somatic KRAS mutations that appear among the strong resistance hits. Our study positions future drug discovery targeting KRASG12C toward focusing on inhibitors preserving potency against resistance mutations at key residues.