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

Chiara Pozzato1, Gonçalo Outeiro-Pinho1, Mirco Galiè2

  • 1Institute of Pharmacology, University of Bern, 3010, Bern, Switzerland.

EMBO Molecular Medicine
|September 13, 2024
PubMed

Insights

Targeting extracellular-signal-regulated kinase 5 (ERK5) and cyclin-dependent kinase 5 (CDK5) can overcome resistance to Focal Adhesion Kinase (FAK) inhibitors in KRAS-mutant non-small cell lung cancer (NSCLC). This combination therapy enhances anti-tumor responses by promoting cancer cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Mutated KRAS drives 30% of non-small cell lung cancers (NSCLCs), often leading to metastatic and therapy-resistant tumors.
  • Focal Adhesion Kinase (FAK) is crucial for maintaining KRAS-driven lung tumors, but FAK inhibitors show limited long-term efficacy.
  • Understanding resistance mechanisms to FAK inhibitors is critical for improving treatment outcomes in NSCLC.

Purpose of the Study:

  • To identify key mediators of FAK-driven KRAS-mutant NSCLC maintenance.
  • To investigate the role of FAK interactors, ERK5 and CDK5, in tumor progression and therapy resistance.
  • To evaluate the therapeutic potential of inhibiting ERK5 and CDK5 in combination with FAK inhibitors.

Main Methods:

  • Identified FAK interactors ERK5 and CDK5 using molecular biology techniques.
  • Inhibited ERK5 and CDK5 individually and synergistically to assess effects on FAK signaling, proliferation, and apoptosis.
  • Utilized a mouse model of KrasG12D-driven lung adenocarcinoma to evaluate combined pharmacological inhibition.
  • Assessed the impact of ERK5 inhibition on FAK inhibitor resistance and DNA damage.

Main Results:

  • ERK5 and CDK5 were identified as key players in FAK-mediated KRAS-mutant NSCLC.
  • Combined inhibition of ERK5 and CDK5 synergistically suppressed FAK function, reduced proliferation, and induced apoptosis via increased ROS-induced DNA damage.
  • Concomitant pharmacological inhibition of ERK5 and CDK5 suppressed tumor progression and promoted cancer cell death in a KrasG12D mouse model.
  • Cancer cells resistant to FAK inhibitors exhibited increased ERK5-FAK signaling; ERK5 inhibition prevented resistance development and enhanced anti-tumor efficacy.

Conclusions:

  • ERK5 and CDK5 are critical mediators in KRAS-mutant NSCLC maintenance and FAK inhibitor resistance.
  • Combined inhibition of ERK5 and CDK5 represents a promising strategy to overcome FAK inhibitor resistance in NSCLC.
  • Targeting ERK5 alongside FAK could significantly enhance anti-tumor responses and improve long-term outcomes for NSCLC patients.
Keywords:
Combination TherapyDrug ResistanceFAK and ERK5 InhibitorsFocal AdhesionsLung Cancer

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