MTAP Loss Is Frequent in Oncogene-Driven NSCLC and May Confer Sensitivity to Combined PRMT5 Inhibitors and Targeted Therapies - PubMed
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- #PRMT5 inhibition
- #MTAP loss
- #Oncogene-driven NSCLC
- MTAP loss is common in oncogene-driven NSCLC, especially in ALK-, RET-, and EGFR-altered subtypes.
- MTAP loss occurs in 15% of cancers, leading to partial PRMT5 inhibition and vulnerability to PRMT5 inhibitors.
- MTAP loss was found in 17-45% of ALK-rearranged, RET-rearranged, and EGFR-mutant NSCLC cases, often co-deleted with CDKN2A.
- MTAP loss did not significantly affect response or survival in EGFR and ALK-driven NSCLC treated with osimertinib or alectinib.
- PRMT5 inhibitor BMS-986504 showed nanomolar activity in 11/18 MTAP-deleted models, including EGFR and ALK-driven ones.
- Combining BMS-986504 with targeted therapies showed synergistic or additive effects in preclinical models.
- In resistant models, BMS-986504 combined with alectinib or osimertinib improved antitumor activity without toxicity.