National Cancer Institute 1R21CA296234-01A1

Exploratory studies of cellular resistance to MTA-cooperative PRMT5 inhibitors in MTAP-loss tumors.

The award supports research on cellular resistance mechanisms to MTA-cooperative PRMT5 inhibitors in tumors with MTAP loss, aiming to develop resistance models and identify treatment vulnerabilities.

Description

This project focuses on overcoming resistance to targeted cancer therapies in tumors with specific genetic deletions, aiming to improve treatment outcomes. MTAP is deleted in approximately 15% of all human malignancies and co-occurs in 80-90% of all CDKN2A/CDKN2B-deleted cancers, including lung, gastric, brain, breast, urinary tract, and skin cancers. Inhibition of PRMT5, an arginine methyltransferase, is synthetically lethal to cancer cells with MTAP loss. MTAP loss increases intracellular methylthioadenosine (MTA), which inhibits PRMT5 activity. Second-generation MTA-cooperative PRMT5 inhibitors (MTA:PRMT5i) target MTA-bound PRMT5 and show improved selectivity for MTAP loss, with promising early clinical trial results. However, resistance (innate and acquired) remains a challenge. This project aims to develop models of resistance and identify vulnerabilities and molecular signatures associated with resistance. Project goals include establishing in vitro and in vivo models of MTAP-loss tumors resistant to MTA:PRMT5i, evaluating combination treatments with MEK inhibitors, and identifying molecular signatures associated with resistance.

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