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 identified 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 11, 2023
- Source ID
- 10.1073/pnas.2221448120
Entities
People
- Alejandro Barrera
- Annie Liu
- Christian G. Cerda-Smith
- Christopher V. Nicchitta
- Haley M. Hutchinson
- Hazel X. Ang
- Holly Kim
- Ian C. McDowell
- Jiaxing Lin
- Kris C Wood
- Luke C. Bartelt
- Natalia Sutiman
- Qiang Chen
- Timothy E. Reddy
- Xinyue L. Deng
- Zhecheng Sheng
Organizations
- Agency for Science, Technology and Research
- Duke Cancer Institute
- Duke University
- National Institutes of Health
- United States Department of Defense