CCNE1

This study aimed to develop a mutational signature-based biomarker (MSBM) to define homologous recombination deficiency (HRD) in advanced ovarian cancer, overcoming limitations of genomic scar-based assays. The MSBM integrates tumor-BRCA mutation status, Mutational Signature 3 similarity score, and the absence of CCNE1 amplification, derived from whole-exome sequencing. A phase II trial (MSBM-OL) validated this biomarker and evaluated the efficacy of olaparib maintenance monotherapy in HRD-positive patients. The study demonstrated that olaparib significantly extended progression-free survival (22.3 months) compared to a predefined 9-month threshold, confirming its clinical benefit as first-line maintenance therapy.

Synthetic lethality describes a genetic interaction where two specific genetic alterations together impair cell viability, while either alteration alone is compatible with survival. This concept offers promising therapeutic avenues for targeting previously undruggable cancer pathways. High-throughput screening technologies have facilitated the discovery of novel druggable synthetic lethal vulnerabilities, particularly in DNA damage response and epigenetic alterations. Clinically approved PARP inhibitors have validated this approach in BRCA-mutant cancers. Emerging strategies targeting PRMT5, MAT2A, WRN, PKMYT1, and WEE1 are currently undergoing late preclinical or early clinical evaluation.