PRMT5

Homozygous MTAP loss is frequently observed in oncogene-driven non-small-cell lung cancers (NSCLC), particularly in EGFR, ALK, and RET altered subtypes. While this loss did not significantly impact the response to first-line targeted therapies, it creates a selective vulnerability to PRMT5 inhibitors. Preclinical studies demonstrated that the PRMT5 inhibitor BMS-986504 is active in MTAP-deleted NSCLC models and can enhance the efficacy of existing targeted therapies. These findings suggest a novel combined therapeutic strategy for NSCLC patients with MTAP loss.

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.