Response to Lehrer

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To the Editor:

We thank Dr Lehrer for his thoughtful correspondence and The Cancer Genome Atlas (TCGA) based analysis of CDK12, MED1, and ERBB2 expression.1 Dr Lehrer’s findings reinforce the close association between CDK12 and MED1 across breast cancer subtypes and extend discussion on the context-dependent CDK12 dysregulation in HER2-positive and ER-positive/HER2-negative disease.

As noted, CDK12 and MED1 show strong co-expression even independent of ERBB2 copy number. This supports our mechanistic evidence that CDK12 functionally cooperates with MED1 and ER to sustain transcription in advanced ER-positive tumors. Although transcriptomic correlations highlight potential co-regulation, our study demonstrated that CDK12 directly influences ER chromatin recruitment and transcriptional output, and this is critical to understanding the functional hierarchy between CDK12, MED1, and ER signaling.

We agree that the proposed dual model of genomic co-amplification in HER2-positive cancers and transcriptional co-activation in ER-positive/HER2-negative cancers offers a useful framework. Clinical series of HER2-positive breast cancers have similarly shown recurrent ERBB2/CDK12 co-amplification and linked it to therapeutic outcome,2^,^3 which supports the genomic dosage context described by Dr Lehrer. Moreover, targeting CDK12 in HER2-amplified models reduces PI3K/AKT signaling and restores anti-HER2 sensitivity,4^,^5 also confirming functional cooperation between CDK12 and HER2 pathways.

Beyond receptor-positive disease, pharmacological studies in triple-negative breast cancer have demonstrated that dual CDK12/CDK13 inhibition provokes intronic polyadenylation, suppresses DNA-damage-repair gene expression, and induces a “BRCAness” phenotype that sensitizes tumors to PARP inhibitors and platinum agents.6^,^7

These observations indicate that CDK12 can regulate distinct transcriptional programs depending on molecular context, including genomic co-amplification in HER2-positive disease, CDK12/MED1-driven co-activation in luminal tumors, and potential DNA-repair gene control in basal-like disease (Figure 1). In practice, distinguishing between these contexts will be essential when designing therapeutic strategies that target the CDK12 complex, because these mechanisms may not be mutually exclusive.