MTAP loss is frequent in oncogene-driven NSCLC and may confer sensitivity to combined PRMT5 inhibitors and targeted therapies.
Summary
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.
Analysis
Clinique: This retrospective study on large NSCLC cohorts identifies MTAP loss as a frequent biomarker in oncogene-driven subtypes (EGFR, ALK, RET). While MTAP loss alone was not predictive of response to current first-line targeted therapies, preclinical data suggest it could identify patients who might benefit from a combination of PRMT5 inhibitors and targeted therapies. This would justify phase I/II clinical trials to evaluate this combination, with a potential clinical impact in 5+ years. Biomol: The key discovery is that MTAP loss, often co-deleted with CDKN2A, leads to partial PRMT5 inhibition, creating a selective vulnerability. The study validates the activity of the PRMT5 inhibitor BMS-986504 in preclinical models (in vitro, ex vivo, in vivo) of MTAP-deleted NSCLC, regardless of targeted therapy sensitivity. The technologies used, NGS and IHC, are established methods for MTAP status assessment, which facilitates the potential translation of this biomarker.