CRISPR-Mediated Kinome Editing Prioritizes a Synergistic Combination Therapy for FGFR1-Amplified Lung Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Fibroblast Growth Factor Receptor (FGFR) pathway activation is common in lung and other cancers.
• Drug resistance limits the clinical benefit of FGFR-targeted therapies in FGFR-amplified tumors.
• Mechanisms underlying FGFR inhibitor resistance are not fully understood.

Purpose of the Study:

• To identify novel targets that mediate resistance to FGFR inhibitors.
• To investigate the role of Polo-like kinase 1 (PLK1) in FGFR inhibitor resistance.
• To evaluate the therapeutic potential of combining FGFR and PLK1 inhibition.

Main Methods:

• Kinome-wide CRISPR/Cas9 loss-of-function screens in FGFR1-amplified lung cancer cells.
• Treatment with an FGFR inhibitor.
• Genetic and pharmacological inhibition of PLK1.
• Assessment of antiproliferative effects and cancer cell death in vitro and in vivo.
• Analysis of the γH2AX-CHK-E2F1 signaling axis.

Main Results:

• PLK1 was identified as a synthetic lethal target mediating resistance to FGFR inhibition.
• PLK1 inhibition overrides DNA damage and cell-cycle arrest induced by FGFR inhibition.
• Combined PLK1 and FGFR inhibition synergistically enhanced anti-cancer effects and induced cell death.
• The synergistic effect was mediated through the activation of the γH2AX-CHK-E2F1 axis.

Conclusions:

• PLK1 plays a critical role in modulating sensitivity to FGFR inhibitors.
• Combined inhibition of PLK1 and FGFR represents a promising therapeutic strategy for FGFR1-amplified lung cancer.
• This study provides a novel rationale for treating lung and other FGFR1-amplified cancers.