Data from Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRAS&lt;sup&gt;G12C&lt;/sup&gt; Inhibitor Efficacy

Ziyan Lin,Benjamin G Neel,Yi Jer Tan,Soumyadip Sahu,Yeuan Ting Lee,Yingzhuo Liu,Shuai Li,Alireza Khodadadi-Jamayran,Kwok-Kin Wong,Hsin-Yi Huang,Michela Ranieri,James G Christensen,Suman Mukhopadhyay,Hai Hu,Fiona Sherman,Tinghu Zhang,Igor Dolgalev,Vamsidhar Velcheti,Alfonso Lopez,Kayla Guidry,Priyanka Sahu,Wenchao Lu,Tracy T Tang,Amanda P Armstrong,Nathanael S Gray,Yi Ban

doi:10.1158/0008-5472.c.6982720

Abstract

<div>AbstractNon–small lung cancers (NSCLC) frequently (∼30%) harbor KRAS driver mutations, half of which are KRASG12C. KRAS-mutant NSCLC with comutated STK11 and/or KEAP1 is particularly refractory to conventional, targeted, and immune therapy. Development of KRASG12C inhibitors (G12Ci) 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.Significance:Identification of synthetic lethal genes with KRASG12C using genome-wide CRISPR/Cas9 screening and credentialing of the ability of TEAD inhibition to enhance KRASG12C efficacy provides a roadmap for combination strategies.<a href="https://aacrjournals.org/cancerres/article/doi/10.1158/0008-5472.CAN-23-3547" target="_blank">See related commentary by Johnson and Haigis, p. 4005</a></div>

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