Development of Combination Strategies for Focal Adhesion Kinase Inhibition in Diffuse Gastric Cancer

作者全名："Peng, Ke; Zhang, Feifei; Wang, Yichen; Sahgal, Pranshu; Li, Tianxia; Zhou, Jin; Liang, Xiaoyan; Zhang, Yanxi; Sethi, Nilay; Liu, Tianshu; Zhang, Haisheng; Bass, Adam J."

作者地址："[Peng, Ke; Liu, Tianshu] Fudan Univ, Zhongshan Hosp, Dept Med Oncol, Shanghai, Peoples R China; [Peng, Ke; Zhang, Feifei; Wang, Yichen; Sahgal, Pranshu; Li, Tianxia; Zhou, Jin; Liang, Xiaoyan; Zhang, Yanxi; Sethi, Nilay; Zhang, Haisheng] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA; [Wang, Yichen] Fudan Univ, Shanghai Canc Ctr, Dept Pathol, Shanghai, Peoples R China; [Li, Tianxia; Bass, Adam J.] Columbia Univ, Dept Med, Div Hematol & Oncol, Irving Med Ctr, New York, NY USA; [Zhou, Jin] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Dept Liver Surg & Liver Transplantat, Chengdu, Peoples R China; [Zhou, Jin] Sichuan Univ, West China Hosp, Canc Ctr, Chengdu, Peoples R China; [Zhou, Jin] Collaborat Innovat Ctr Biotherapy, Chengdu, Peoples R China; [Liang, Xiaoyan] Chongqing Med Univ, Dept Gastroenterol, Affiliated Hosp 1, Chongqing, Peoples R China; [Zhang, Haisheng] Southern Med Univ, Nanfang Hosp, Dept Gen Surg, Guangzhou, Peoples R China; [Bass, Adam J.] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Vagelos Coll Phys & Surg, 1130 St Nicholas Ave, New York, NY 10032 USA; [Zhang, Haisheng] Southern Med Univ, Nanfang Hosp, 1838 Guangzhou Blvd N, Guangzhou 510515, Guangdong, Peoples R China"

通信作者："Bass, AJ (通讯作者)，Columbia Univ, Herbert Irving Comprehens Canc Ctr, Vagelos Coll Phys & Surg, 1130 St Nicholas Ave, New York, NY 10032 USA.; Zhang, HS (通讯作者)，Southern Med Univ, Nanfang Hosp, 1838 Guangzhou Blvd N, Guangzhou 510515, Guangdong, Peoples R China."

来源：CLINICAL CANCER RESEARCH

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000907954600001

JCR分区：Q1

影响因子：10

年份：2023

卷号：29

期号：1

开始页：197

结束页：208

文献类型：Article

关键词：　

摘要："Purpose: Diffuse gastric cancer (DGC) is an aggressive and frequently lethal subtype of gastric cancer. Because DGC often lacks genomic aberrations that indicate clear candidate therapeutic targets, it has been challenging to develop targeted therapies for this gastric cancer subtype. Our previous study highlighted the contri-bution of focal adhesion kinase (FAK) in the tumorigenesis of DGC and the potential efficacy of small-molecule FAK inhibitors. How-ever, drug resistance to monotherapy often hinders the efficacy of treatment. Experimental Design: We generated a genome-scale library of open reading frames (ORF) in the DGC model of Cdh1-/-RHOAY42C/+/- organoids to identify candidate mechanisms of resistance to FAK inhibition. Compensatory activated pathways were also detected following treatment with FAK inhibitors. Candidates were inves-tigated by cotargeting in vitro and in vivo experiments using DGC. Results: We found that cyclin-dependent kinase 6 (CDK6) promoted FAK inhibitor resistance in ORF screen. In addition, FAK inhibitor treatment in DGC models led to compensatory MAPK pathway activation. Small-molecule CDK4/6 inhibitors or MAPK inhibitors effectively enhanced FAK inhibitor efficacy in vitro and in vivo. Conclusions: Our data suggest that FAK inhibitors combined with MAPK inhibitors or CDK4/6 inhibitors warrant further testing in clinical trials for DGC."

基金机构：V Foundation; NIH [R01 CA224428]

基金资助正文："We thank Prof. David Root for valuable suggestions regarding the analysis of ORF screen data. Verastem Oncology kindly provided VS -4718 and VS -6766. This work was supported by The V Foundation (to A.J. Bass) and the NIH (R01 CA224428, to A.J. Bass) ."