Combined inhibition of Bcl-2 family members and YAP induces synthetic lethality in metastatic gastric cancer with RASA1 and NF2 deficiency

Molecular Cancer

Research

Dominic C. Voon¹  Jeong-Seop Oh²  Dae-Yong Kim²  Taehun Ha³  Gyeong Min Yoon³  Sang Hyeok Seok³  Hyeok-Won An³  Jong-Wan Kwon³  Hyeon Ah Kim³  Sung Eun Kim³  Pu-Reum Oh³  Jun Won Park³  Yu Jin Lee³  Na Yun Lee³  Su-Hyung Lee⁴ 

[1] Cancer Research Institute, Kanazawa University, 920-1192, Kanazawa, Ishikawa, Japan;Innovative Cancer Model Research Unit, Institute for Frontier Science Initiative, Kanazawa University, 920-1192, Kanazawa, Ishikawa, Japan;Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, 1, Gwanak-Ro, Gwanak-Gu, 08826, Seoul, Republic of Korea;Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, 08826, Seoul, Republic of Korea;Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, 1, Kangwondaehak-Gil, 24341, Chuncheon-Si, Gangwon-Do, Republic of Korea;Section of Surgical Sciences, Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA;

关键词: Cancer stem cells;    CRISPR/Cas9;    Wnt pathway;    YAP signaling;   

DOI  :  10.1186/s12943-023-01857-0

 received in 2023-05-05, accepted in 2023-09-05,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundTargetable molecular drivers of gastric cancer (GC) metastasis remain largely unidentified, leading to limited targeted therapy options for advanced GC. We aimed to identify molecular drivers for metastasis and devise corresponding therapeutic strategies.MethodsWe performed an unbiased in vivo genome-wide CRISPR/Cas9 knockout (KO) screening in peritoneal dissemination using genetically engineered GC mouse models. Candidate genes were validated through in vivo transplantation assays using KO cells. We analyzed target expression patterns in GC clinical samples using immunohistochemistry. The functional contributions of target genes were studied through knockdown, KO, and overexpression approaches in tumorsphere and organoid assays. Small chemical inhibitors against Bcl-2 members and YAP were tested in vitro and in vivo.ResultsWe identified Nf2 and Rasa1 as metastasis-suppressing genes through the screening. Clinically, RASA1 mutations along with low NF2 expression define a distinct molecular subtype of metastatic GC exhibiting aggressive traits. NF2 and RASA1 deficiency increased in vivo metastasis and in vitro tumorsphere formation by synergistically amplifying Wnt and YAP signaling in cancer stem cells (CSCs). NF2 deficiency enhanced Bcl-2-mediated Wnt signaling, conferring resistance to YAP inhibition in CSCs. This resistance was counteracted via synthetic lethality achieved by simultaneous inhibition of YAP and Bcl-2. RASA1 deficiency amplified the Wnt pathway via Bcl-xL, contributing to cancer stemness. RASA1 mutation created vulnerability to Bcl-xL inhibition, but the additional NF2 deletion conferred resistance to Bcl-xL inhibition due to YAP activation. The combined inhibition of Bcl-xL and YAP synergistically suppressed cancer stemness and in vivo metastasis in RASA1 and NF2 co-deficiency.ConclusionOur research unveils the intricate interplay between YAP and Bcl-2 family members, which can lead to synthetic lethality, offering a potential strategy to overcome drug resistance. Importantly, our findings support a personalized medicine approach where combined therapy targeting YAP and Bcl-2, tailored to NF2 and RASA1 status, could effectively manage metastatic GC.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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