Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling
Abstract KRAS mutation is one of the most prevalent genetic drivers of cancer development, yet KRAS mutations are until very recently considered undruggable. There are ongoing trials of drugs that target the KRAS G12C mutation, yet acquired drug resistance from the extended use has already become a...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-08-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202100250 |
| _version_ | 1818645988031594496 |
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| author | Baoyuan Zhang Yan Zhang Jiangwei Zhang Ping Liu Bo Jiao Zaiqi Wang Ruibao Ren |
| author_facet | Baoyuan Zhang Yan Zhang Jiangwei Zhang Ping Liu Bo Jiao Zaiqi Wang Ruibao Ren |
| author_sort | Baoyuan Zhang |
| collection | DOAJ |
| description | Abstract KRAS mutation is one of the most prevalent genetic drivers of cancer development, yet KRAS mutations are until very recently considered undruggable. There are ongoing trials of drugs that target the KRAS G12C mutation, yet acquired drug resistance from the extended use has already become a major concern. Here, it is demonstrated that KRAS G12C inhibition induces sustained activation of focal adhesive kinase (FAK) and show that a combination therapy comprising KRAS G12C inhibition and a FAK inhibitor (IN10018) achieves synergistic anticancer effects. It can simultaneously reduce the extent of drug resistance. Diverse CDX and PDX models of KRAS G12C mutant cancer are examined and synergistic benefits from the combination therapy are consistently observed. Mechanistically, it is found that both aberrant FAK–YAP signaling and FAK‐related fibrogenesis impact on the development of KRAS G12C inhibitor resistance. This study thus illustrates the mechanism of resistance of cancer to the treatment of KRAS G12C inhibitor, as well as an innovative combination therapy to improve treatment outcomes for KRAS G12C mutant cancers. |
| first_indexed | 2024-12-17T00:39:29Z |
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| id | doaj.art-a31d96a1af6c4b72ab49e6db22443a6f |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-12-17T00:39:29Z |
| publishDate | 2021-08-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj.art-a31d96a1af6c4b72ab49e6db22443a6f2022-12-21T22:10:03ZengWileyAdvanced Science2198-38442021-08-01816n/an/a10.1002/advs.202100250Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP SignalingBaoyuan Zhang0Yan Zhang1Jiangwei Zhang2Ping Liu3Bo Jiao4Zaiqi Wang5Ruibao Ren6Shanghai Institute of Hematology State Key Laboratory for Medical Genomics National Research Center for Translational Medicine International Center for Aging and Cancer Collaborative Innovation Center of Hematology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200025 ChinaShanghai Institute of Hematology State Key Laboratory for Medical Genomics National Research Center for Translational Medicine International Center for Aging and Cancer Collaborative Innovation Center of Hematology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200025 ChinaInxMed (Shanghai) Co., Ltd Shanghai 201202 ChinaShanghai Institute of Hematology State Key Laboratory for Medical Genomics National Research Center for Translational Medicine International Center for Aging and Cancer Collaborative Innovation Center of Hematology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200025 ChinaShanghai Institute of Hematology State Key Laboratory for Medical Genomics National Research Center for Translational Medicine International Center for Aging and Cancer Collaborative Innovation Center of Hematology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200025 ChinaInxMed (Shanghai) Co., Ltd Shanghai 201202 ChinaShanghai Institute of Hematology State Key Laboratory for Medical Genomics National Research Center for Translational Medicine International Center for Aging and Cancer Collaborative Innovation Center of Hematology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200025 ChinaAbstract KRAS mutation is one of the most prevalent genetic drivers of cancer development, yet KRAS mutations are until very recently considered undruggable. There are ongoing trials of drugs that target the KRAS G12C mutation, yet acquired drug resistance from the extended use has already become a major concern. Here, it is demonstrated that KRAS G12C inhibition induces sustained activation of focal adhesive kinase (FAK) and show that a combination therapy comprising KRAS G12C inhibition and a FAK inhibitor (IN10018) achieves synergistic anticancer effects. It can simultaneously reduce the extent of drug resistance. Diverse CDX and PDX models of KRAS G12C mutant cancer are examined and synergistic benefits from the combination therapy are consistently observed. Mechanistically, it is found that both aberrant FAK–YAP signaling and FAK‐related fibrogenesis impact on the development of KRAS G12C inhibitor resistance. This study thus illustrates the mechanism of resistance of cancer to the treatment of KRAS G12C inhibitor, as well as an innovative combination therapy to improve treatment outcomes for KRAS G12C mutant cancers.https://doi.org/10.1002/advs.202100250drug resistanceFAKKRAS G12CsynergyYAP |
| spellingShingle | Baoyuan Zhang Yan Zhang Jiangwei Zhang Ping Liu Bo Jiao Zaiqi Wang Ruibao Ren Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling Advanced Science drug resistance FAK KRAS G12C synergy YAP |
| title | Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling |
| title_full | Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling |
| title_fullStr | Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling |
| title_full_unstemmed | Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling |
| title_short | Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling |
| title_sort | focal adhesion kinase fak inhibition synergizes with kras g12c inhibitors in treating cancer through the regulation of the fak yap signaling |
| topic | drug resistance FAK KRAS G12C synergy YAP |
| url | https://doi.org/10.1002/advs.202100250 |
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