Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy

被引：35

作者：

Mukhopadhyay, Suman ^{[1
]}

Huang, Hsin-Yi ^{[1
]}

Lin, Ziyan ^{[2
]}

Ranieri, Michela ^{[1
]}

Li, Shuai ^{[1
]}

Sahu, Soumyadip ^{[1
]}

Liu, Yingzhuo ^{[1
]}

Ban, Yi ^{[1
]}

Guidry, Kayla ^{[1
]}

Hu, Hai ^{[1
]}

Lopez, Alfonso ^{[1
]}

Sherman, Fiona ^{[1
]}

Tan, Yi Jer ^{[1
]}

Lee, Yeuan Ting ^{[1
]}

Armstrong, Amanda P. ^{[1
]}

Dolgalev, Igor ^{[1
]}

Sahu, Priyanka ^{[1
]}

Zhang, Tinghu ^{[3
]}

Lu, Wenchao ^{[3
]}

Gray, Nathanael S. ^{[3
]}

Christensen, James G. ^{[4
]}

Tang, Tracy T. ^{[5
]}

Velcheti, Vamsidhar ^{[1
]}

Khodadadi-Jamayran, Alireza ^{[2
]}

Wong, Kwok-Kin ^{[1
]}

Neel, Benjamin G. ^{[1
,6
]}

机构：

[1] NYU Langone Hlth, Laura & Isaac Perlmutter Canc Ctr, NYU Grossman Sch Med, New York, NY USA

[2] NYU, Appl Bioinformat Labs, Off Sci & Res, Grossman Sch Med, New York, NY USA

[3] Stanford Univ, Stanford Canc Inst, Sch Med, Dept Chem & Syst Biol,ChEM H, Stanford, CA USA

[4] Mirati Therapeut Inc, San Diego, CA USA

[5] Vivace Therapeut Inc, San Mateo, CA USA

[6] NYU, Perlmutter Canc Ctr, Dept Med, Grossman Sch Med, 522 First Ave, New York, NY 10016 USA

来源：

CANCER RESEARCH | 2023年 / 83卷 / 24期

基金：

美国国家卫生研究院;

关键词：

SET ENRICHMENT ANALYSIS; DRIVEN CANCERS; RAS; RESISTANCE; PATHWAY; YAP/TAZ; GROWTH; RHOA; COMBINATION; ACTIVATION;

D O I：

10.1158/0008-5472.CAN-23-2729

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Non-small lung cancers (NSCLC) frequently (similar to 30%) harbor KRAS driver mutations, half of which are KRAS(G12C). KRAS-mutant NSCLC with comutated STK11 and/or KEAP1 is particularly refractory to conventional, targeted, and immune therapy. Development of KRAS(G12C) 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 KRAS(G12C) using genome-wide CRISPR/Cas9 screening and credentialing of the ability of TEAD inhibition to enhance KRAS(G12C) efficacy provides a roadmap for combination strategies.

引用

页码：4095 / 4111

页数：17

共 22 条

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