{'fraction_non_alphanumeric': 0.021861777150916785, 'fraction_numerical': 0.014104372355430184, 'mean_word_length': 5.7894736842105265, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Cooperative regulation of coupled oncoprotein translation and stability in triple-negative breast cancer by EGFR and CDK12

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.