cd-23-0669_supplementary_table_s2_suppst2.xlsx (13.76 MB)

Supplementary Table S2 from MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer

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posted on 2023-11-01, 08:01 authored by Lars D. Engstrom, Ruth Aranda, Laura Waters, Krystal Moya, Vickie Bowcut, Laura Vegar, David Trinh, Allan Hebbert, Christopher R. Smith, Svitlana Kulyk, J. David Lawson, Leo He, Laura D. Hover, Julio Fernandez-Banet, Jill Hallin, Darin Vanderpool, David M. Briere, Alice Blaj, Matthew A. Marx, Jordi Rodon, Michael Offin, Kathryn C. Arbour, Melissa L. Johnson, David J. Kwiatkowski, Pasi A. Jänne, Candace L. Haddox, Kyriakos P. Papadopoulos, Jason T. Henry, Konstantinos Leventakos, James G. Christensen, Ronald Shazer, Peter Olson

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Funding

Mirati Therapeutics (Mirati Therapeutics Inc)

History

ARTICLE ABSTRACT

Previous studies implicated protein arginine methyltransferase 5 (PRMT5) as a synthetic lethal target for MTAP-deleted (MTAP del) cancers; however, the pharmacologic characterization of small-molecule inhibitors that recapitulate the synthetic lethal phenotype has not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with >70-fold selectivity in HCT116 MTAP del compared with HCT116 MTAP wild-type (WT) cells. MRTX1719 demonstrated dose-dependent antitumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts or hematopoietic cells. MRTX1719 demonstrated marked antitumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non–small cell lung cancer, and malignant peripheral nerve sheath tumors from the phase I/II study. PRMT5 was identified as a synthetic lethal target for MTAP del cancers; however, previous PRMT5 inhibitors do not selectively target this genotype. The differentiated binding mode of MRTX1719 leverages the elevated MTA in MTAP del cancers and represents a promising therapy for the ∼10% of patients with cancer with this biomarker.See related commentary by Mulvaney, p. 2310.This article is featured in Selected Articles from This Issue, p. 2293

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Keywords

Biomarkers Genetic biomarkers Drug Mechanisms Cellular responses to anticancer drugs Drug Targets Oncoprotein & tumor suppressor drug targets Pharmacology Pharmacogenetics/pharmacogenomics Precision Medicine Small Molecule Agents HDAC & methyltransferase inhibitors

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CC BY