American Association for Cancer Research
can-23-2729_supplementary_figures_1-7_suppsf1-sf7.pdf (85.25 MB)

Supplementary Figures 1-7 from Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy

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posted on 2024-04-04, 15:20 authored by Suman Mukhopadhyay, Hsin-Yi Huang, Ziyan Lin, Michela Ranieri, Shuai Li, Soumyadip Sahu, Yingzhuo Liu, Yi Ban, Kayla Guidry, Hai Hu, Alfonso Lopez, Fiona Sherman, Yi Jer Tan, Yeuan Ting Lee, Amanda P. Armstrong, Igor Dolgalev, Priyanka Sahu, Tinghu Zhang, Wenchao Lu, Nathanael S. Gray, James G. Christensen, Tracy T. Tang, Vamsidhar Velcheti, Alireza Khodadadi-Jamayran, Kwok-Kin Wong, Benjamin G. Neel

Supplementary Figures 1-7 including Figure legends


National Institutes of Health (NIH)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Non–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. 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.See related commentary by Johnson and Haigis, p. 4005

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