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 CDK12 dramatically sensitizes diverse models of TNBC to EGFR blockade. Instead of functioning through CDK12′s well-established roles proximal to transcription, this combination therapy drives cell death through the 4E-BP1-dependent suppression of the translation and consequent stability 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, rescuing MYC translational suppression and 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 reveals a long proposed EGFR dependence in TNBC that functions through the cooperative regulation of translation-coupled oncoprotein stability.

中文翻译：

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EGFR和CDK12对三联阴性乳腺癌中癌蛋白翻译和稳定性的协同调节

长期以来的证据表明，表皮生长因子受体（EGFR）可能在三​​阴性乳腺癌（TNBC）发病机理中起着重要作用，但是EGFR抑制剂的临床试验却产生了令人失望的结果。使用候选药物筛选，我们发现对CDK12的抑制极大地使TNBC的多种模型对EGFR阻断敏感。这种组合疗法不是通过CDK12在转录附近的公认角色来发挥功能，而是通过4E-BP1依赖性翻译抑制和驱动程序癌蛋白（包括MYC）的稳定性来驱动细胞死亡。全基因组的CRISPR / Cas9筛选将CCR4-NOT复合物确定为对联合治疗敏感的主要决定因素，该联合治疗的丧失使4E-BP1对药物诱导的去磷酸化反应无反应，拯救MYC的翻译抑制和稳定性。在自然进化出治疗耐药性的TNBC细胞中观察到CNOT1丢失和4E-BP1磷酸化的恢复，进一步强调了CCR4-NOT和4E-BP1在联合治疗中的核心作用。因此，CDK12的药理抑制作用揭示了TNBC中长期存在的EGFR依赖性，该依赖性通过翻译偶联癌蛋白稳定性的协同调节发挥作用。