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Proximity Labeling reveals role of 14-3-3 protein YWHAB in CDK4/6 inhibitors resistance in breast cancer

ABSTRACT: CDK4/6 inhibitors are currently standard of care for advanced hormone positive (HR+) breast cancer, and CDK6 overexpression induces resistance against CDK4/6 inhibitors. We incidentally discovered that overexpression of a CDK6 D224Y mutant mitigated this resistance. Mechanistic studies revealed that CDK6 overexpression resulted in suppressed apoptosis and increased G1/S progression after treatment with CDK4/6 inhibitors; these features were abolished when CDK6 D224Y was overexpressed. Proximity labeling proteomics revealed CDK6 overexpression, but not CDK6 D224Y overexpression, induced binding of the 14-3-3 protein YWHAB. Co-immunoprecipitation experiments confirmed YWHAB bound overexpressed wild type CDK6 but not CDK6 D224Y, and YWHAB knockdown decreased CDK6 protein expression in a proteosomal dependent manner. Knockdown of YWHAB reversed the resistance conferred by CDK6 amplification. Xenograft studies confirmed that CDK6 D224Y overexpression reversed the resistance conferred by CDK6 overexpression in vivo. In summary, by studying CDK6 D224Y, we uncovered a role for YWHAB that modulates CDK4/6 inhibitor resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282062 | GEO | 2025/11/11

REPOSITORIES: GEO

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Project description:Cdk4 and Cdk6 are two related kinases that bind D-type cyclins and regulate cell cycle progression. Due to their relevance in cancer, Cdk4/6 inhibitors are currently in advanced clinical trials in multiple tumor types. Cdk4/6 are inhibited by INK4 proteins that exert tumor suppressing functions. To test the significance of this inhibitory mechanism we have generated knock-in mice that express a Cdk6 mutant (Cdk6 R31C) insensitive to INK4-mediated inhibition. Cdk6R/R mice display altered development of the hematopoietic system without resulting in enhanced tumor susceptibility, either in the presence or absence of p53. The presence of the Cdk6 R31C allele results in defective potential of hematopoietic progenitors in adoptive transfer assays or after induced damage. These defects are rescued after complete insensitivity to INK4 inhibitors in Cdk4R/R; Cdk6R/R double mutant mice, and INK4-resistant mice display increased susceptibility to hematopoietic and endocrine tumors. In BCR-ABL-transformed hematopoietic cells, the presence of the Cdk6 R31C allele results in increased binding of p16INK4a to wild-type Cdk4, whereas the double mutant is fully insensitive to INK4 inhibitors resulting in accelerated disease onset. Our observations reveal that Cdk4 and Cdk6 cooperate in tumor development and suggest a role for Cdk6 in buffering INK4 protein levels thus contributing to the development of hematopoietic tumors. The presence of the Cdk4 R24C and Cdk6 R31C alleles results in relevant changes in the expression profiles of cancer cells including deregulation of apoptosis and other processes. p185BCR-ABL1 was used to transform wild-type or double knock-in Cdk4 R24C; Cdk6 R31C fetal livers. Cell lines were isolated as spontaneous immortal and transformed clones after transduction of fetal liver with a p185 BCR-ABL1-transgene. RNA was isolated from asynchronous cultures. Two-condition experiment, Cdk4R-Cdk6R cells versus wild-type cells. Biological replicates: 3 control replicates, 3 transfected replicates.

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Proximity Labeling reveals role of 14-3-3 protein YWHAB in CDK4/6 inhibitors resistance in breast cancer

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