CRISPR screening identifies mechanisms of resistance to KRASG12C and SHP2 inhibitor combinations in non-small cell lung cancer

by Selleckchem | Jan 23 2024

Although KRASG12C inhibitors show clinical activity in patients with KRAS G12C mutated non-small cell lung cancer (NSCLC) and other solid tumor malignancies, response is limited by multiple mechanisms of resistance. The KRASG12C 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 KRASG12C-mutant NSCLC line and investigated the genetic mechanisms associated with loss of response to combined KRASG12C/SHP2 inhibition. Tumor regression by single-agent JDQ443 at clinically relevant doses lasted on average 2 weeks and was increasingly extended by the double, triple or quadruple combinations. Growth resumption was accompanied by progressively increased KRAS G12C amplification. Functional genome-wide CRISPR screening in KRASG12C-dependent NSCLC lines with distinct mutational profiles to identify adaptive mechanisms of resistance revealed sensitizing and rescuing genetic interactions with KRASG12C/SHP2 co-inhibition; FGFR1 loss was the strongest sensitizer, and PTEN loss the strongest rescuer. Consistently, the antiproliferative activity of KRASG12C/SHP2 inhibition was strongly enhanced by PI3K inhibitors. Overall, KRAS G12C amplification and alterations of the MAPK/PI3K pathway were predominant mechanisms of resistance to combined KRASG12C/SHP2 inhibitors in preclinical settings. The biological nodes identified by CRISPR screening might provide additional starting points for effective combination treatments.

Comments:

The study you're referencing delves into the complexities of combating resistance in KRASG12C-mutated cancers, particularly non-small cell lung cancer (NSCLC), using inhibitors like JDQ443 and TNO155. These inhibitors have shown promise but are hindered by various resistance mechanisms. The research explores combining these inhibitors with others like alpelisib (PI3Kα inhibitor) and ribociclib (CDK4/6 inhibitor) to overcome or prevent resistance.

The findings indicate that while JDQ443 alone caused tumor regression for about two weeks, combining it with TNO155, alpelisib, and ribociclib extended this regression. However, tumor regrowth was observed, often accompanied by increased KRAS G12C amplification. Genetic screenings using CRISPR revealed interactions that either sensitized or rescued cells from KRASG12C/SHP2 co-inhibition. Notably, loss of FGFR1 sensitized cells, while loss of PTEN rescued them. Additionally, PI3K inhibitors significantly enhanced the antiproliferative effects of KRASG12C/SHP2 inhibition.

Overall, KRASG12C amplification and alterations in the MAPK/PI3K pathway were the primary resistance mechanisms observed. The study suggests potential combination treatments targeting specific biological nodes identified through CRISPR screening to address resistance more effectively.

This research underscores the complexity of combating resistance in KRASG12C-mutated cancers and highlights the potential of combination therapies to overcome these challenges. Identifying and targeting specific genetic interactions and pathways could pave the way for more effective treatments for these cancers.