Genome-wide CRISPR screen identified NEK6 as a determinant of sensitivity to CDK4/6 inhibitor in endometrial cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Endometrial cancer (EC) frequently exhibits cell cycle pathway alterations, particularly CCND1/CDK4/6 axis hyperactivation.
• This suggests CDK4/6 inhibitors as a potential therapeutic strategy for EC.

Purpose of the Study:

• To identify genes modulating response to CDK4/6 inhibitors using a genome-wide CRISPR-Cas9 screen.
• To investigate NIMA-related kinase-6 (NEK6) as a potential therapeutic target in EC.

Main Methods:

• Genome-wide CRISPR-Cas9 knockout screen to identify resistance genes.
• In vitro and in vivo studies to evaluate combined NEK6 and CDK4/6 inhibition.
• Mechanistic studies involving protein binding, phosphorylation, and gene transcription analysis.

Main Results:

• NEK6 levels were found to determine the efficacy of CDK4/6 inhibitors in EC.
• NEK6 acts as a synthetic lethal target in combination with CDK4/6 inhibitors.
• Combined NEK6 and CDK4/6 inhibition significantly suppressed tumor growth.
• NEK6 facilitates YBX1 phosphorylation, promoting nuclear translocation and activating CDK2 and bcl2 transcription.

Conclusions:

• NEK6 is a critical determinant of CDK4/6 inhibitor response in endometrial cancer.
• Combined inhibition of NEK6 and CDK4/6 offers a potent anti-tumor strategy.
• These findings provide preclinical evidence for clinical trials of combination therapy in EC patients.