Details

Autor(en) / Beteiligte

• Ang, Hazel X
• Sutiman, Natalia
• Deng, Xinyue L
• Liu, Annie
• Cerda-Smith, Christian G
• Hutchinson, Haley M
• Kim, Holly
• Bartelt, Luke C
• Chen, Qiang
• Barrera, Alejandro
• Lin, Jiaxing
• Sheng, Zhecheng
• McDowell, Ian C
• Reddy, Timothy E
• Nicchitta, Christopher V
• Wood, Kris C

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2023-09, Vol.120 (38), p.e2221448120-e2221448120

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.