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Early Clinical Success of MTA-Cooperative PRMT5 Inhibitors for the Treatment of CDKN2A/MTAP-Deleted Cancers
Kathleen M Mulvaney1,2,3,4,5
1Fralin Biomedical Research Institute, Virginia Polytechnic Institute and State University, Roanoke, Virginia.
Summary:
CDKN2A encodes the tumor suppressors p16 and p14ARF and is the most common homozygously deleted gene in all human cancers; tumors frequently codelete the nearby gene MTAP, creating a dependency on PRMT5. In this issue of Cancer Discovery, Engstrom and colleagues report an MTA-cooperative PRMT5 methyltransferase inhibitor MRTX1719 that selectively kills CDKN2A/MTAP-codeleted cancers and demonstrates early efficacy in clinical trials for solid tumors harboring the CDKN2A/MTAP codeletion. See related article by Engstrom et al., p. 2412 (1).
Insights
A new drug, MRTX1719, shows promise in treating cancers with specific gene deletions (CDKN2A/MTAP). This targeted therapy creates a dependency on PRMT5, offering a new approach for solid tumors.
Area of Science:
- Oncology
- Cancer Genetics
- Pharmacology
Background:
- The CDKN2A gene, encoding tumor suppressors p16 and p14ARF, is frequently deleted in human cancers.
- Co-deletion of the adjacent MTAP gene is common in these cancers, leading to a dependency on the PRMT5 enzyme.
- This genetic vulnerability presents a therapeutic target in specific cancer types.
Purpose of the Study:
- To identify and evaluate a novel therapeutic agent targeting cancers with CDKN2A and MTAP co-deletion.
- To assess the efficacy of the PRMT5 inhibitor MRTX1719 in preclinical models and early clinical trials.
Main Methods:
- Development of an MTA-cooperative PRMT5 methyltransferase inhibitor, MRTX1719.
- Testing the drug's selective killing of cancer cells with CDKN2A/MTAP co-deletion.
- Evaluating early clinical trial data for solid tumors harboring this specific genetic alteration.
Main Results:
- MRTX1719 selectively eliminates cancer cells with the CDKN2A/MTAP co-deletion.
- Early clinical trials demonstrate promising efficacy in patients with solid tumors exhibiting this genetic profile.
- The drug exploits a specific metabolic vulnerability created by the gene co-deletion.
Conclusions:
- MRTX1719 is a promising targeted therapy for cancers with CDKN2A/MTAP co-deletion.
- This inhibitor offers a novel therapeutic strategy by targeting PRMT5 dependency.
- Further clinical investigation is warranted to confirm efficacy and safety in a broader patient population.
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