Antiproliferative activity of PRMT5 inhibitor monotherapy and in combination with tyrosine kinase inhibitors (TKIs) was evaluated in MTAP-deleted NSCLC cell lines harboring <i>EGFR</i> or <i>KRAS</i> mutations or <i>ALK</i> rearrangements.<h4>Results</h4>Among 243 NSCLC specimens from 240 patients (72% with driver alterations, 90% adenocarcinoma), MTAP loss was identified in 43 (18%) specimens from 40 (17%) patients, including 18 (14%) early-stage and 22 (20%) metastatic tumors. Here, PRMT5 is linked to adenocarcinoma.