MTAP Loss Is Frequent in Oncogene-Driven NSCLC and May Confer Sensitivity to Combined PRMT5 Inhibitors and Targeted Therapies.

[BACKGROUND] Homozygous loss of MTAP (methylthioadenosine phosphorylase) occurs in approximately 15% of cancers and leads to partial PRMT5 inhibition, creating a selective vulnerability to PRMT5 inhibitors. The frequency and therapeutic relevance of MTAP loss in oncogene-driven non-small cell lung cancers (NSCLCs) remain underexplored.

[METHODS] MTAP status was assessed by next-generation sequencing (NGS) or immunohistochemistry (IHC) in >13,000 NSCLC samples in four cohorts. Prevalence was assessed across oncogenic drivers and temporal dynamics in pre- and post-treatment biopsies. Clinical outcomes were analyzed in EGFR- and ALK-rearranged NSCLC treated with first-line osimertinib and alectinib, respectively. The MTA-cooperative PRMT5 inhibitor BMS-986504 was tested alone and in combination with targeted therapies (TT) in MTAP-deleted models in vitro, ex vivo and in vivo.

[RESULTS] MTAP loss was frequent in ALK-rearranged (27% and 33% by NGS; 36% and 45% IHC), RET-rearranged (18.5% and 26% by NGS; 35% by IHC), and EGFR-mutant NSCLC (17% and 24% by NGS; 24% and 29% by IHC), with CDKN2A co-deletion in 98% of cases. MTAP loss was typically present prior to TT. MTAP loss did not significantly impact response or overall survival with first-line osimertinib or alectinib in EGFR mutant and ALK-rearranged NSCLC, respectively. In preclinical studies, BMS-986504 showed nanomolar activity in 11/18 MTAP-deleted models, including 5/8 EGFR- and 5/5 ALK-driven models, regardless of TT sensitivity. Synergistic or additive effects with TT were observed in 11/18 models. In ex vivo ALK-rearranged spheroids resistant to crizotinib, the combination of BMS-986504 and alectinib improved antitumor activity over monotherapy. In an osimertinib-resistant, EGFR mutant PDX model, BMS-986504 with or without osimertinib controlled tumor growth, without weight loss.

[CONCLUSIONS] MTAP loss is frequent in oncogene-driven NSCLC, particularly in ALK-, RET-, and EGFR-altered subtypes. MTA-cooperative PRMT5 inhibition demonstrates broad activity in MTAP-deleted, oncogene-driven models and, and may enhance targeted therapy efficacy in selected settings.