Transcriptomics

Dataset Information

0

Cooperative regulation of coupled oncoprotein synthesis and stability in triple-negative breast cancer by EGFR and CDK12/13


ABSTRACT: Evidence has long suggested that epidermal growth factor receptor (EGFR) may play a prominent role in triple-negative breast cancer (TNBC) pathogenesis, but clinical trials of EGFR inhibitors have yielded disappointing results. Using a candidate drug screen, we discovered that inhibition of cyclin-dependent kinases 12 and 13 (CDK12/13) dramatically sensitizes diverse models of TNBC to EGFR blockade. This combination therapy drives cell death through the 4E-BP1-dependent suppression of the translation and translation-linked turnover of driver oncoproteins, including MYC. A genome-wide CRISPR/Cas9 screen identified the CCR4-NOT complex as a major determinant of sensitivity to the combination therapy whose loss renders 4E-BP1 unresponsive to drug-induced dephosphorylation, thereby rescuing MYC translational suppression and promoting MYC stability. The central roles of CCR4-NOT and 4E-BP1 in response to the combination therapy were further underscored by the observation of CNOT1 loss and rescue of 4E-BP1 phosphorylation in TNBC cells that naturally evolved therapy resistance. Thus, pharmacological inhibition of CDK12/13 reveals a long proposed EGFR dependence in TNBC that functions through the cooperative regulation of translation-coupled oncoprotein stability.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221475 | GEO | 2023/09/27

REPOSITORIES: GEO

Dataset's files

Source:
Action DRS
Other
Items per page:
1 - 1 of 1

Similar Datasets

2023-03-09 | GSE224287 | GEO
2019-06-14 | GSE131668 | GEO
2023-03-27 | GSE227978 | GEO
2024-01-31 | GSE254472 | GEO
| MSV000086059 | MassIVE
2023-05-10 | PXD033301 | Pride
| PRJNA1068585 | ENA
2010-12-08 | E-GEOD-25904 | biostudies-arrayexpress
2018-07-18 | GSE117240 | GEO
2019-09-18 | GSE137553 | GEO