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ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer

ABSTRACT: Mutated KRAS serves as the oncogenic driver in 30% of non-small cell lung cancers (NSCLCs) and is associated with metastatic and therapy-resistant tumors. Focal Adhesion Kinase (FAK) acts as a mediator in sustaining KRAS-driven lung tumors, and although FAK inhibitors are currently undergoing clinical development, clinical data indicated that their efficacy in producing long-term anti-tumor responses is limited. Here we revealed two FAK interactors, extracellular-signal-regulated kinase 5 (ERK5) and cyclin-dependent kinase 5 (CDK5), as key players underlying FAK-mediated maintenance of KRAS mutant NSCLC. Inhibition of ERK5 and CDK5 synergistically suppressed FAK function, decreased proliferation and induced apoptosis owing to exacerbated ROS-induced DNA damage. Accordingly, concomitant pharmacological inhibition of ERK5 and CDK5 in a mouse model of KrasG12D-driven lung adenocarcinoma suppressed tumor progression and promoted cancer cell death. Cancer cells resistant to FAK inhibitors showed enhanced ERK5-FAK signaling dampening DNA damage. Notably, ERK5 inhibition prevented the development of resistance to FAK inhibitors, significantly enhancing the efficacy of antitumor responses. Therefore, we propose ERK5 inhibition as a potential co-targeting strategy to counteract FAK inhibitor resistance in NSCLC.

SUBMITTER: Prof. Georgia Konstantinidou

PROVIDER: S-SCDT-10_1038-S44321-024-00138-7 | biostudies-other |

REPOSITORIES: biostudies-other

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ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer [p826_PND_A549]

Project description:Mutated KRAS serves as the oncogenic driver in 30% of non-small cell lung cancers (NSCLCs) and is associated with metastatic and therapy-resistant tumors. Focal Adhesion Kinase (FAK) acts as a mediator in sustaining KRAS-driven lung tumors, and although FAK inhibitors are currently undergoing clinical development, clinical data indicated that their efficacy in producing long-term anti-tumor responses is limited. Here we revealed two FAK interactors, extracellular-signal-regulated kinase 5 (ERK5) and cyclin-dependent kinase 5 (CDK5) as key players underlying FAK-mediated maintenance of KRAS mutant NSCLC. Inhibition of ERK5 and CDK5 synergistically suppressed FAK function, decreased proliferation and induced apoptosis owing to exacerbated ROS-induced DNA damage. Accordingly, concomitant pharmacological inhibition of ERK5 and CDK5 in a mouse model of KrasG12D-driven lung adenocarcinoma suppressed tumor progression and promoted cancer cell death. Cancer cells resistant to FAK inhibitors showed enhanced ERK5-FAK signaling dampening DNA damage. Notably, ERK5 inhibition prevents resistance to FAK inhibitors, significantly enhancing the efficacy of antitumor responses. Therefore, we propose ERK5 inhibition as a potential co-targeting strategy to counteract FAK inhibitor resistance in NSCLC.

2024-09-16 | GSE255643 | GEO

ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer [p697_ERK5]

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ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer [p826_PND_A549]

Project description:ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer [p826_PND_A549]

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ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer [p697_ERK5]

Project description:ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer [p697_ERK5]

| PRJNA1075794 | ENA

Integrin αvβ3 Induces HSP90 Inhibitor Resistance via FAK Activation in KRAS-Mutant Non-Small Cell Lung Cancer.

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miR-1298 Inhibits Mutant KRAS-Driven Tumor Growth by Repressing FAK and LAMB3.

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Therapeutic Suppression of FAK-AKT Signaling Overcomes Resistance to SHP2 Inhibition in Colorectal Carcinoma.

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