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

TL;DR

A CRISPR screen found that NEK6 levels affect how well CDK4/6 inhibitors work in endometrial cancer, suggesting a new treatment strategy.

Contribution

NEK6 is identified as a novel synthetic lethal target for CDK4/6 inhibitors in endometrial cancer.

Findings

NEK6 levels determine the anti-tumor effects of CDK4/6 inhibitors in endometrial cancer.

Combined inhibition of NEK6 and CDK4/6 suppresses tumor growth in vitro and in vivo.

NEK6 promotes YBX1 phosphorylation and activation of CDK2 and bcl2 transcription.

Abstract

Endometrial cancer (EC) harbors highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of CDK4/6 inhibitors in these cancers. In this study, we performed a genome-wide CRISPR-Cas9-based knockout screen to identify genes that modify the response to CDK4/6 inhibitors. We found that NIMA-related kinase-6 (NEK6) levels determine the anti-tumor effects of CDK4/6 inhibitors and that NEK6 was a synthetic lethal target of CDK4/6 inhibitors in EC. We further demonstrated that combined inhibition of NEK6 and CDK4/6 resulted in marked suppression of tumor growth in vitro and in vivo. Mechanistically, NEK6 bound to Y-box binding protein-1 (YBX1) in the cytoplasm and facilitated its phosphorylation at serine 102 (p-YBX1S102), which promoted YBX1 nuclear translocation and further activated CDK2 and bcl2 transcription. As such, these data provided robust pre-clinical mechanistic evidence of synergy between NEK6 and CDK4/6 inhibitors and delineated a path for translation of these findings to preliminary clinical studies in EC patients.

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