Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy.
Suman MukhopadhyayHsin-Yi HuangZiyan LinMichela RanieriShuai LiSoumyadip SahuYingzhuo LiuYi BanKayla GuidryHai HuAlfonso LopezFiona ShermanYi Jer TanYeuan Ting LeeAmanda P ArmstrongIgor DolgalevPriyanka SahuTinghu ZhangWen Chao LuNathanael S GrayJames G ChristensenTracy T TangVamsidhar VelchetiAlireza Khodadadi-JamayranKwok-Kin WongBenjamin G NeelPublished in: Cancer research (2023)
Non-small lung cancers (NSCLCs) frequently (~30%) harbor KRAS driver mutations, half of which are KRASG12C. KRAS-mutant NSCLC with co-mutated STK11 and/or KEAP1 is particularly refractory to conventional, targeted, and immune therapy. Development of KRASG12C inhibitors (G12Cis) provided a major therapeutic advance, but resistance still limits their efficacy. To identify genes whose deletion augments efficacy of the G12Cis adagrasib (MRTX-849) or adagrasib plus TNO155 (SHP2i), we performed genome-wide CRISPR/Cas9 screens on KRAS/STK11-mutant NSCLC lines. Recurrent, potentially targetable, synthetic lethal (SL) genes were identified, including serine-threonine kinases, tRNA-modifying and proteoglycan synthesis enzymes, and YAP/TAZ/TEAD pathway components. Several SL genes were confirmed by siRNA/shRNA experiments, and the YAP/TAZ/TEAD pathway was extensively validated in vitro and in mice. Mechanistic studies showed that G12Ci treatment induced gene expression of RHO paralogs and activators, increased RHOA activation, and evoked ROCK-dependent nuclear translocation of YAP. Mice and patients with acquired G12Ci- or G12Ci/SHP2i-resistant tumors showed strong overlap with SL pathways, arguing for the relevance of the screen results. These findings provide a landscape of potential targets for future combination strategies, some of which can be tested rapidly in the clinic.
Keyphrases
- genome wide
- wild type
- dna methylation
- gene expression
- crispr cas
- copy number
- small cell lung cancer
- advanced non small cell lung cancer
- protein kinase
- cancer therapy
- primary care
- high throughput
- mesenchymal stem cells
- multidrug resistant
- stem cells
- skeletal muscle
- high fat diet induced
- small molecule
- adipose tissue
- young adults
- metabolic syndrome
- combination therapy
- brain metastases
- replacement therapy
- climate change
- smoking cessation
- genome wide identification
- protein protein