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Targeting Cyclin K-CDK12 Synergizes with ATR Inhibition by Limiting RPA Chromatin Loading in Triple-Negative Breast Cancer

ABSTRACT: Cyclin K-CDK12 inhibition has emerged as a promising therapeutic strategy to induce homologous recombination deficiency (HRD). However, clinical and genomic studies have not clearly linked CDK12 inactivation to HRD. Here, we demonstrate that cyclin K-CDK12 depletion drives a replication stress (RS)-associated vulnerability through RPA regulation. A DNA damage response-focused CRISPR screen identified DNA replication factors and ATR activators as top sensitizers to cyclin K degradation. Consistently, cyclin K-CDK12 depletion synergized with ATR inhibition in triple-negative breast cancer (TNBC) models. Cyclin K degradation reduces RPA chromatin loading and impairs ATR activation, compromising cellular tolerance to RS and increasing susceptibility to ATR inhibition. We show that CDK12-mediated phosphorylation of CDC5L is required for RPA chromatin loading and mediates resistance to combined cyclin K and ATR depletion. Our findings identify cyclin K-CDK12 as a critical regulator of RPA dynamics and support its inhibition as rational therapy for RS-high tumors, including TNBC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328758 | GEO | 2026/04/26

REPOSITORIES: GEO

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Targeting Cyclin K-CDK12 Synergizes with ATR Inhibition by Limiting RPA Chromatin Loading in Triple-Negative Breast Cancer [ChIP-seq]

Project description:Cyclin K-CDK12 inhibition has emerged as a promising therapeutic strategy to induce homologous recombination deficiency (HRD). However, clinical and genomic studies have not clearly linked CDK12 inactivation to HRD. Here, we demonstrate that cyclin K-CDK12 depletion drives a replication stress (RS)-associated vulnerability through RPA regulation. A DNA damage response-focused CRISPR screen identified DNA replication factors and ATR activators as top sensitizers to cyclin K degradation. Consistently, cyclin K-CDK12 depletion synergized with ATR inhibition in triple-negative breast cancer (TNBC) models. Cyclin K degradation reduces RPA chromatin loading and impairs ATR activation, compromising cellular tolerance to RS and increasing susceptibility to ATR inhibition. We show that CDK12-mediated phosphorylation of CDC5L is required for RPA chromatin loading and mediates resistance to combined cyclin K and ATR depletion. Our findings identify cyclin K-CDK12 as a critical regulator of RPA dynamics and support its inhibition as rational therapy for RS-high tumors, including TNBC.

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