Skip to content
    Oncology Data Advisor Logo
    Real-World Studies

    MTAP Loss Prevalence and PRMT5 Inhibitor Activity in Oncogene-Driven and Oncogene-Negative NSCLC

    Sakai et alClinical cancer research : an official journal of the American Association for Cancer Research

    MTAP Loss Prevalence and PRMT5 Inhibitor Activity in Oncogene-Driven and Oncogene-Negative NSCLC
    In non-small cell lung cancer (NSCLC), MTAP loss co-occurs with actionable genomic alterations and creates a therapeutic vulnerability to protein arginine methyltransferase 5 (PRMT5) inhibition. Because estimates of MTAP loss based on next-generation sequencing may underestimate copy loss, MTAP expression was evaluated using immunohistochemistry (IHC) in 243 NSCLC specimens from 240 patients (72% harboring driver alterations, 90% adenocarcinoma; 132 early-stage, 111 metastatic), including 33 specimens with paired lymph nodes.
    MTAP loss was identified in 42 (17%) specimens overall, including 17 (13%) early-stage and 22 (20%) metastatic tumors. Among stage 4 cases, MTAP loss was identified in 24% of driver-positive NSCLCs compared with 14% of driver-negative tumors (p=0.314). Analysis of 33 lung-nodal pairs showed concordance in 21 (64%) cases, whereas 8 cases exhibited decreased MTAP expression only in lymph nodes.
    Preclinical evaluation of PRMT5 inhibitor monotherapy and combination therapy with tyrosine kinase inhibitors (TKIs) was conducted across 22 MTAP-deleted NSCLC cell lines (9 EGFR-mutant, 7 KRAS-mutant, 6 ALK-rearranged). Variable sensitivity to PRMT5 inhibition was observed, with responses occurring in both TKI-sensitive and TKI-resistant cell lines. Symmetric dimethylarginine (SDMA) expression did not predict PRMT5 inhibitor sensitivity. Combinations of TKIs and PRMT5 inhibitors had greater activity than monotherapy, supporting evaluation of PRMT5 inhibitors combined with TKIs in oncogene-driven NSCLC.

    Key Takeaways

    • MTAP loss was identified by immunohistochemistry in 17% (42/243) of NSCLC specimens overall, occurring in 13% of early-stage tumors, 20% of metastatic tumors, and 24% of stage 4 driver-positive tumors versus 14% of driver-negative tumors (p=0.314).
    • In 22 MTAP-deleted NSCLC cell lines harboring EGFR, KRAS, or ALK alterations, PRMT5 inhibitors showed activity across both TKI-sensitive and TKI-resistant models, with TKI plus PRMT5 inhibitor combinations demonstrating greater activity than monotherapy.
    Read the original sourceClinical cancer research : an official journal of the American Association for Cancer Research