HRD (Homologous Recombination Deficiency)

PARP enzymes regulate AR via MARylation and PARylation, with inhibitors such as Olaparib, which disrupts AR-PARP crosstalk...We also discuss how this complex regulatory network may contribute to the development of advanced prostate cancer therapies in the future. This could improve PARP inhibitor and AR signalling inhibitor combinations and allow more patients to benefit from them.

No significant differences were observed between QuANTUM, the GT and the AmoyDx tool in identifying cases with tumor cellularity above or below the method-defined 30% cutoff. Considering its high reliability, the QuANTUM algorithm may serve as a robust tool for ensuring adequate TCF evaluation in HGSC.

Notably, our structural contact analysis reveals how contact connectivity controls ligand selectivity, providing valuable mechanistic and molecular insight into the key residues that stabilize each inhibitor in both protein enzymes. Together, our multimethod computational study contributes to elucidating potential chemical modifications across the ligand chemical space to enhance potency and specificity, informing the future design and evaluation of selective inhibitors for precision oncology, including therapies targeting homologous recombination-deficient cancers.

Targeting genomic instability has reshaped oncology: first through systemic chemotherapy and external beam radiation and then with poly(ADP-ribose) polymerase (PARP) inhibitors in homologous recombination repair-deficient tumors and other DNA damage response targets. Recently, tumor-targeted DNA-damaging platforms, namely antibody-drug conjugates (ADCs) and radiopharmaceuticals, have emerged alongside modern precision medicine strategies to optimize patient selection, develop rational combinations, and widen the therapeutic index.

The tumor-only algorithm demonstrated an equivalent capacity to the paired sample algorithm for classifying HRD status in ovarian cancer. This algorithm also showed cross-racial applicability, highlighting its potential for clinical use.

However, many patients with these variants have urothelial cancer of the bladder only. Broader genetic testing, particularly in those with a suggestive personal or family cancer history, may help identify patients at risk who might otherwise be missed.

Furthermore, liquid biopsy profiling, PSMA‑positron emission tomography‑based radiomics and artificial intelligence platforms are enhancing real‑time patient selection and response assessment. The present review synthesized these recent preclinical and clinical advances to delineate biomarker‑driven, mechanism‑based therapeutic sequencing and combination strategies for mCRPC in the post‑ARPI era.19.

MAICs showed improved clinical benefit with TALA+ENZA versus OLAP+AAP and NIRA+AAP across multiple mCRPC populations and endpoints. Despite limitations of indirect comparisons, findings support TALA+ENZA as a first-line treatment option for mCRPC.

Functional analysis in cell lines suggests poly (ADP-ribose) polymerase inhibitors and cytotoxic chemotherapy sensitivity in HRD and CN tumors, whereas immune features in MUT tumors support vulnerability to immunotherapy. These findings suggest that distinct hBC subtypes delineated by genomic instability can advance insights into molecular heterogeneity beyond expression-based classifications and support an integrative genomic instability index (HRD score, ploidy, size-stratified CN burden, and signature exposures) for patient stratification and personalized therapeutic strategies.

Patient-derived glioma stem-like cells (GSCs), treated with PRMT5 inhibitor (LLY-283) or transfected with PRMT5-target-specific siRNA, were treated with TMZ and subjected to in vitro functional and mechanistic studies. Furthermore, compared to monotherapy, there was a significant reduction in the proliferation marker Ki-67, while the apoptosis marker cleaved caspase 3 and the DNA damage response marker γH2AX were upregulated. Collectively, these findings identify PRMT5 as a critical regulator of the FA pathway in glioblastoma and demonstrate that PRMT5 inhibition potentiates TMZ efficacy by disrupting FA-dependent homologous recombination repair, indicating that the combination of PRMT5 inhibition and TMZ could be a novel therapeutic strategy for glioblastoma.

Subsequently, we explore how olaparib treatment itself can alter the expression profile of ncRNAs, creating a dynamic feedback loop that may influence therapeutic outcome. By consolidating these findings across various cancers, including ovarian, breast, prostate, and hepatocellular carcinoma, this review highlights the potential of ncRNAs as both predictive biomarkers and therapeutic targets to overcome PARPi resistance and enhance patient outcomes.

CT imaging features were associated with HRD status and prognosis in HGSOC, and the proposed CT-based classification showed fair discriminatory performance.