Aims: Although KRAS G12C inhibitors show clinical activity in patients with KRAS G12C mutated Non-Small Cell Lung Cancer (NSCLC) and other solid tumor malignancies, the response is limited by multiple mechanisms of resistance. The KRAS G12C inhibitor JDQ443 shows enhanced preclinical antitumor activity combined with the SHP2 inhibitor TNO155, and the combination is currently under clinical evaluation. To identify rational combination strategies that could help overcome or prevent some types of resistance, we evaluated the duration of tumor responses to JDQ443 ± TNO155, alone or combined with the PI3Kα inhibitor alpelisib and/or the CDK4/6 inhibitor ribociclib, in xenograft models derived from a KRAS G12C-mutant NSCLC cell-line and investigated the genetic mechanisms associated with loss of response to combined KRAS G12C/SHP2 inhibition.

Methods: Low-pass whole-genome sequencing (lp-WGS), RNA-seq

Targets: LU99 tumor-bearing mice treated with either vehicle or quadruple combination regiment (JDQ443 + TNO155 + alpelisib + ribociclib)