Prahallad, Anirudh, Weiss, Andreas, Voshol, Johannes, Kerr, Grainne, Yuan, Tina, Ruddy, David, Meistertzheim, Morgane, Kazic-Legueux, Malika, Kottarathil, Tina, Piquet, Michelle, Cao, Yichen, Martinuzzi-Duboc, Laetitia, Buhles, Alexandra, reimann, flavia, Mannino, Salvatore, Laurent, Sansregret, Tordella, Luca, Fedele, Carmine, Maira, Michel, Graus Porta, Diana, Brachmann, Saskia and Sprouffske, Kathleen (2023) Mechanisms of tumor resistance to clinically relevant KRASG12C and SHP2 inhibitor combination in preclinical models of non-small cell lung cancer. Mechanisms of tumor resistance to clinically relevant KRASG12C and SHP2 inhibitor combination in preclinical models of non-small cell lung cancer, 83 (24). pp. 4130-4141.

Abstract

Although KRASG12C inhibitors have shown clear clinical activity in patients with KRAS G12C mutated NSCLC and other solid tumor malignancies, the depth and durability of responses is limited by multiple mechanisms of treatment-emergent resistance. The KRASG12C inhibitor JDQ443 shows enhanced preclinical antitumor activity combined with the SHP2 inhibitor TNO155. We evaluated the duration of response in a mouse model to JDQ443 ± TNO155 (± the PI3Ka inhibtor alpelisib and/or the CDK4/6 inhibitor ribociclib), and the genetic mechanisms associated with loss of response to a KRASG12C/SHP2 inhibitor combination. Antitumor responses to JDQ443 ± TNO155, with or without additional alpelisib and/or ribociclib, were assessed in cell-derived mouse xenograft models derived from the KRASG12C-mutant non-small cell lung cancer (NSCLC) line LU99. Single-agent tumor regression by JDQ443 at clinical relevant doses of 100 mg/kg in the LU99 model was on average 2 weeks and was increasingly extended (but not prevented) by JDQ443 dual-agent, triple or quadruple on-pathway combinations. Growth resumption was accompanied by increased KRASG12C gene copy number and expression. Adaptive mechanisms of resistance to KRASG12C/SHP2 co-inhibition were explored by functional genome-wide CRISPR screening in KRASG12C-dependent NSCLC lines with distinct mutational profiles. CRISPR screening in a panel of 5 KRAS G12C-mutated cell lines identified sensitizing and rescuing genetic interactions to a KRASG12C/SHP2 inhibitor combination; FGFR1 was the strongest sensitizer, and PTEN the strongest rescuer. Consistent with this, KRASG12C/SHP2 inhibitor antiproliferative activity was strongly enhanced by PI3K inhibitors. Amplification of KRAS G12C itself and alterations of the MAPK/PI3K pathway were the predominant mechanisms of resistance to KRASG12C/SHP2 co-inhibition in this model. Biological nodes identified by CRISPR screening might provide starting points for effective combination treatment approaches.

Item Type:	Article
Keywords:	RAS, KRAS G12C, JDQ443, combinations, resistance, SHP2, TNO155
Date Deposited:	09 Jul 2024 00:46
Last Modified:	09 Jul 2024 00:46
URI:	https://oak.novartis.com/id/eprint/51573