RPA2 (Replication Protein A2)

Platinum resistant ovarian cancer cells were depleted for RPA 1 or 2 and tested for cisplatin, olaparib and talazoparib sensitivity. HAMNO monotherapy was cytotoxic to sensitive and resistant cells. We conclude that RPA directed precision oncology strategy could be a viable strategy in HGSOC.

The overexpression of miR-139-3p in BC cells enhanced cisplatin, olaparib, and irradiation (IR) sensitivity. The diagnostic model based on the four circulating miRNAs could serve as a tool for the liquid biopsy of BC. Targeting the miR-139-3p/RPA2 axis may have potential in modulating the DNA damage pathway in BC.

Silencing APOBEC3B reduced RPA2 and ASF1B levels and suppressed TGF-β signaling. These findings identify APOBEC3B/ASF1B as a central pathway through which HPV infection activates TGF-β signaling and promotes EMT, offering potential biomarkers and therapeutic targets for high-risk HPV-positive OPC.

Furthermore, NKX2-1 positive cells showed less induction of DNA damage and apoptosis upon treatment with etoposide, a DNA damaging chemotherapy agent that is clinically used to treat T-ALL...Notably, NKX2-1 expressing cells showed higher sensitivity towards RUNX1 inhibition, suggesting a cooperative role in regulating T-ALL cell survival. This work reveals a critical role of NKX2-1 in enhancing T-ALL cell survival through DNA damage protection, and identifies RUNX1 as an important cofactor in T-ALL pathogenesis.

Together, our findings provide a comprehensive overview of the HR pathway in HNSCC, highlighting the dual role of HR proteins in both genomic maintenance and immune regulation. The consistent upregulation of HR proteins, their association with disease progression, and potential immunogenic effects underscore their promise as diagnostic/prognostic biomarkers and therapeutic targets in HNSCC.

Importantly, both genetic and pharmacologic disruption of the GSK3B-53BP1 axis sensitizes tumors to PARP inhibitors (PARPi) independently of BRCA1 status. Together, these findings reveal a GSK3B-dependent mechanism that regulates DSB repair pathway choice and provide a rationale for targeting this axis to enhance PARPi efficacy in solid tumors regardless of BRCA1 status.

These surprising results suggest that GSK3β may select between NHEJ and HR DNA repair pathways. Additionally, these data support targeting the GSK3β/53BP1 axis to enhance PARP inhibitor efficacy in solid tumors, regardless of BRCA1 status.

Our findings revealed that nuclear Pfn1 acts as a tumor suppressor by inhibiting DNA replication and cell growth, while cytoplasmic Pfn1 promotes tumorigenesis by enhancing stemness and replication efficiency. These results highlight the dual role of Pfn1 in breast cancer progression, governed by its subcellular localization. They suggested that modulating Pfn1 nuclear-cytoplasmic shuttling may be a potential therapeutic strategy.

HDAC7 depletion also reduces BRCA2 expression and increases cancer cell sensitivity to DNA-damaging agents. These findings reveal HDAC7's role in the euchromatic H3.3 chaperone network and the impact of HDAC7 depletion on chromatin dynamics, epigenetic restriction, and DNA damage in cancer cells.

Gemcitabine induces nuclear cGAS accumulation independent of STING-mediated immune activation. The binding of nuclear cGAS to γH2AX at double strand DNA breaks (DSBs) plays a pivotal role in RS activation and mitotic catastrophe in gemcitabine and AZD6738 treated cells.

TTK protein kinase (TTK) has been implicated in cisplatin resistance in OC, but its role in PARPi resistance remains unclear. In conclusion, TTK inhibition overcomes olaparib resistance in HR-proficient OC cells, in part by suppressing RPA2-S33 phosphorylation and attenuating ATR signaling. TTK inhibitors offer a promising strategy to increase the therapeutic efficacy of PARPis in OC patients.

Furthermore, we demonstrated that P-AscH- augments the cytotoxic effects of standard-of-care temozolomide and synergistically enhances the anticancer effects of mTOR inhibitors...Collectively, our findings suggest that P-AscH- disrupts both DDR and mTOR signaling pathways, potentially sensitizing GBM cells to both existing therapies and investigational drugs. These results underscore the promise of P-AscH- as an adjunctive treatment for GBM and other malignancies.