Lung cancer, a leading cause of cancer-related mortality, is often driven by mutations in the key oncogenes epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma virus (KRAS). Despite advancements of targeted therapies such as tyrosine kinase inhibitors, resistance remains a significant hurdle. Overexpression of HER3, associated with poor prognosis in non-small cell lung cancer (NSCLC), presents an alternative therapeutic target. In this study, we investigate the efficacy of the HER3-targeting antibody-drug conjugate HER3-DXd and its synergistic potential when combined with cell cycle and DNA damage response modulators. A significant synergy is observed with PARP inhibitors, effective in both EGFR- and KRAS-mutated NSCLC models. This combination markedly enhances DNA damage, induces apoptosis, and slows down in vivo tumor progression. Notably, this regimen also triggers antibody-dependent immunomodulatory effects through cGAS-STING pathway activation, potentiating innate immune cells for tumor killing. Our findings suggest that combining HER3-DXd with PARP inhibitors offers a promising therapeutic approach, effectively targeting diverse NSCLC subtypes.
Linh Lin, Narges Moradi, I. Lähdeniemi et al.· Cell Reports Medicine· 0 citations
CDK12 facilitates transcriptional elongation and processivity by RNA polymerase II (Pol II). Although it has emerged as a promising actor and target in cancer, better understanding of CDK12 gene transcription control could inform the design of novel anti-cancer strategies. Here, we identify a co-dependency between CDK12 and the BAF chromatin-remodeling complex in triple-negative breast cancer (TNBC). Genome-scale CRISPR interference screening revealed multiple BAF subunits as strong dependencies upon CDK12 inhibition. In turn, pharmacological co-targeting of CDK12 and BAF ATPase synergistically reduced the viability of multiple TNBC models. Mechanistically, the co-inhibition attenuated di-phosphorylation of the Pol II C-terminal domain at Serine-2 and Serine-5 and depleted canonical pre-mRNA 3′-end processing factors from chromatin, driving accumulation of chromatin-associated Pol II, upstream of apoptosis. Whereas BAF inhibition rapidly reduced transcription-coupled DNA accessibility, CDK12 inhibition imposed a gene length-biased transcriptional defect exacerbated by BAF deficiency. In turn, co-inhibited cells, marked by synergistic induction of MYC and repression of long cell-cycle and mitotic genes, showed a failure of DNA synthesis and mitotic entry, culminating in MYC-mediated apoptosis. Together, our findings reveal a regulatory axis in which impaired Pol II elongation creates a heightened requirement for BAF-dependent chromatin remodeling. This discovered co-dependency provides a rationale for co-targeting the CDK12-BAF axis in transcriptionally addicted cancers.
M. Mačáková, Cassidy Danyko, Stefan Oberlin et al.· bioRxiv· 0 citations
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