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Synergism of FAK and ROS1 inhibitors in the treatment of CDH1-deficient cancers mediated by FAK-YAP signaling

CDH1 deficiency is common in diffuse gastric cancer and triple negative breast cancer patients, both of which still lack effective therapeutics. ROS1 inhibition results in synthetic lethality in CDH1-deficient cancers, but often leads to adaptive resistance. Here, we demonstrate that upregulation of...

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Autores principales: Gao, Jiaming, Yao, Yunying, Liu, Chenxuan, Xie, Xi, Li, Donghe, Liu, Ping, Wang, Zaiqi, Zhang, Baoyuan, Ren, Ruibao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10266074/
https://www.ncbi.nlm.nih.gov/pubmed/37324948
http://dx.doi.org/10.7150/ijbs.81918
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author Gao, Jiaming
Yao, Yunying
Liu, Chenxuan
Xie, Xi
Li, Donghe
Liu, Ping
Wang, Zaiqi
Zhang, Baoyuan
Ren, Ruibao
author_facet Gao, Jiaming
Yao, Yunying
Liu, Chenxuan
Xie, Xi
Li, Donghe
Liu, Ping
Wang, Zaiqi
Zhang, Baoyuan
Ren, Ruibao
author_sort Gao, Jiaming
collection PubMed
description CDH1 deficiency is common in diffuse gastric cancer and triple negative breast cancer patients, both of which still lack effective therapeutics. ROS1 inhibition results in synthetic lethality in CDH1-deficient cancers, but often leads to adaptive resistance. Here, we demonstrate that upregulation of the FAK activity accompanies the emergence of resistance to ROS1 inhibitor therapy in gastric and breast CDH1-deficient cancers. FAK inhibition, either by FAK inhibitors or by knocking down its expression, resulted in higher cytotoxicity potency of the ROS1 inhibitor in CDH1-deficient cancer cell lines. Co-treatment of mice with the FAK inhibitor and ROS1 inhibitors also showed synergistic effects against CDH1-deficient cancers. Mechanistically, ROS1 inhibitors induce the FAK-YAP-TRX signaling, decreasing oxidative stress-related DNA damage and consequently reducing their anti-cancer effects. The FAK inhibitor suppresses the aberrant FAK-YAP-TRX signaling, reinforcing ROS1 inhibitor's cytotoxicity towards cancer cells. These findings support the use of FAK and ROS1 inhibitors as a combination therapeutic strategy in CDH1-deficient triple negative breast cancer and diffuse gastric cancer patients.
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spelling pubmed-102660742023-06-15 Synergism of FAK and ROS1 inhibitors in the treatment of CDH1-deficient cancers mediated by FAK-YAP signaling Gao, Jiaming Yao, Yunying Liu, Chenxuan Xie, Xi Li, Donghe Liu, Ping Wang, Zaiqi Zhang, Baoyuan Ren, Ruibao Int J Biol Sci Research Paper CDH1 deficiency is common in diffuse gastric cancer and triple negative breast cancer patients, both of which still lack effective therapeutics. ROS1 inhibition results in synthetic lethality in CDH1-deficient cancers, but often leads to adaptive resistance. Here, we demonstrate that upregulation of the FAK activity accompanies the emergence of resistance to ROS1 inhibitor therapy in gastric and breast CDH1-deficient cancers. FAK inhibition, either by FAK inhibitors or by knocking down its expression, resulted in higher cytotoxicity potency of the ROS1 inhibitor in CDH1-deficient cancer cell lines. Co-treatment of mice with the FAK inhibitor and ROS1 inhibitors also showed synergistic effects against CDH1-deficient cancers. Mechanistically, ROS1 inhibitors induce the FAK-YAP-TRX signaling, decreasing oxidative stress-related DNA damage and consequently reducing their anti-cancer effects. The FAK inhibitor suppresses the aberrant FAK-YAP-TRX signaling, reinforcing ROS1 inhibitor's cytotoxicity towards cancer cells. These findings support the use of FAK and ROS1 inhibitors as a combination therapeutic strategy in CDH1-deficient triple negative breast cancer and diffuse gastric cancer patients. Ivyspring International Publisher 2023-05-15 /pmc/articles/PMC10266074/ /pubmed/37324948 http://dx.doi.org/10.7150/ijbs.81918 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Gao, Jiaming
Yao, Yunying
Liu, Chenxuan
Xie, Xi
Li, Donghe
Liu, Ping
Wang, Zaiqi
Zhang, Baoyuan
Ren, Ruibao
Synergism of FAK and ROS1 inhibitors in the treatment of CDH1-deficient cancers mediated by FAK-YAP signaling
title Synergism of FAK and ROS1 inhibitors in the treatment of CDH1-deficient cancers mediated by FAK-YAP signaling
title_full Synergism of FAK and ROS1 inhibitors in the treatment of CDH1-deficient cancers mediated by FAK-YAP signaling
title_fullStr Synergism of FAK and ROS1 inhibitors in the treatment of CDH1-deficient cancers mediated by FAK-YAP signaling
title_full_unstemmed Synergism of FAK and ROS1 inhibitors in the treatment of CDH1-deficient cancers mediated by FAK-YAP signaling
title_short Synergism of FAK and ROS1 inhibitors in the treatment of CDH1-deficient cancers mediated by FAK-YAP signaling
title_sort synergism of fak and ros1 inhibitors in the treatment of cdh1-deficient cancers mediated by fak-yap signaling
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10266074/
https://www.ncbi.nlm.nih.gov/pubmed/37324948
http://dx.doi.org/10.7150/ijbs.81918
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