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

Our plain-English summary of MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer, by L.D. Engstrom, R. Aranda, L. Waters, et al (Cancer Discovery, 2023).

The study

• Authors: L.D. Engstrom, R. Aranda, L. Waters, K. Moya, V. Bowcut, L. Vegar, D. Trinh, A. Hebbert, C.R. Smith, S. Kulyk, J.D. Lawson, L. He, L.D. Hover, J. Fernandez-Banet, J. Hallin, D. Vanderpool, D.M. Briere, A. Blaj, M.A. Marx, J. Rodon, M. Offin, K.C. Arbour, M.L. Johnson, D.J. Kwiatkowski, P.A. Jänne, C.L. Haddox, K.P. Papadopoulos, J.T. Henry, K. Leventakos, J.G. Christensen, R. Shazer, P. Olson
• Journal: Cancer Discovery
• Published: 2023;13(11):2412-2431
• Cited by: 209 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Unlabelled: 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 selecti-vity 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.

Significance: 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.

©2023 The Authors; Published by the American Association for Cancer Research.

In plain English

This article reported laboratory, mouse and early human testing of MRTX1719, an experimental drug designed to block an enzyme called PRMT5 in cancers that have lost a gene called MTAP. The article did not discuss asbestos. In lab-grown colon cancer cells, the drug concentration that cut cell viability by half was 12 nmol/L in cells lacking MTAP, compared with 890 nmol/L in cells with MTAP. Across 70 MTAP-deleted and 26 MTAP-normal cancer cell lines, the median values were 90 nmol/L and 2.2 μmol/L. In mice carrying tumors from five patient-derived mesothelioma models, tumors regressed in four. In a phase I/II trial, the protein mark the enzyme makes (SDMA) became undetectable in tumor cells in biopsies from three patients given 200 mg daily. The authors described six patients whose tumors shrank, selected from 18 evaluable patients. These included two men with epithelioid malignant mesothelioma, whose target lesions shrank by up to 56.1% and by 30.7%. No dose-limiting side effects were seen up to 400 mg daily, though one of these patients' treatment was interrupted for grade 3 diarrhea. The authors concluded that blocking PRMT5 bound to MTA is a rational approach, and they noted that resistance mechanisms are unknown.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Drug development study combining laboratory (cell and biochemical) experiments, mouse tumor xenograft experiments, and early results from a first-in-human phase I/II clinical trial, including six case narratives of responding patients
• Who was studied: Human cancer cell lines, immunocompromised mice bearing human tumor xenografts (including five mesothelioma patient-derived models), and patients with MTAP-deleted solid tumors in trial 1719-001. Six case narratives were selected from 18 patients evaluable for response as of June 13, 2023, at doses of 100 mg daily or more. Two of the six had epithelioid malignant mesothelioma.
• Exposure: The drug MRTX1719, given orally once daily in patients at 50, 100, 200, 400 and 800 mg over 21-day cycles; in mice at doses such as 12.5 to 100 mg/kg daily. Asbestos exposure was not studied.
• Main results:
  • In HCT116 colorectal cancer cells, the IC50 for viability was 12 nmol/L in MTAP-deleted cells and 890 nmol/L in parental (MTAP wild-type) cells.
  • The drug was tested across a panel of 70 MTAP-deleted and 26 MTAP wild-type human cancer cell lines.
  • In that panel, the median IC50 was 90 nmol/L in the MTAP-deleted cell lines and 2.2 μmol/L in the MTAP wild-type cell lines.
  • In five MTAP-deleted mesothelioma patient-derived xenograft models in mice, treatment at 100 mg/kg daily led to regression in four of the five models.
  • In three patients given 200 mg daily, SDMA was undetectable (H-score 0) in tumor cells in cycle 2 day 1 biopsies. Pretreatment H-scores were 240, 250 and 280.
  • A 70-year-old man with epithelioid malignant mesothelioma and pleural disease, given 200 mg daily, had a partial response. His target lesions were reduced by 50.1% and then 56.1% at later assessments.
  • The same patient's lipase and amylase blood levels rose without symptoms after 5 cycles, and treatment was held.
  • An 81-year-old man with unresectable epithelioid malignant mesothelioma, given 200 mg daily, achieved a partial response with a 30.7% reduction of target lesions.
  • In the 81-year-old mesothelioma patient, treatment was interrupted for grade 3 diarrhea during cycle 5.
  • No dose-limiting toxicities were observed at doses up to 400 mg daily; 800 mg daily was still under evaluation.
• The authors' conclusion: The authors concluded that blocking PRMT5 bound to MTA is a rational approach for treating patients whose cancers have this genetic alteration.
• Limitations the authors state:
  • Mechanisms of resistance to MRTX1719 are unknown.
  • It is not yet known whether some tumor types respond better, or whether other biomarkers predict response.
  • Tumor response needs evaluation in a broader patient population with longer follow-up.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: MTAP, Adenocarcinoma, Mesothelioma, Non-Small Cell Lung Cancer, Biomarker.

Related studies

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• Synthetic lethality in malignant pleural mesothelioma with PARP1 inhibition — G. Srinivasan, G.S. Sidhu, et al. (2017)
• BAP1 Malignant Pleural Mesothelioma Mutations in Caenorhabditis elegans Reveal Synthetic Lethality between ubh-4/BAP1 and the Proteasome Subunit rpn-9/PSMD13 — C. Martínez-Fernández, S. Jha, et al. (2023)
• Sulforaphane inhibits PRMT5 and MEP50 function to suppress the mesothelioma cancer cell phenotype — G. Ezeka, G. Adhikary, et al. (2021)
• Adenosine deaminase inhibitor EHNA exhibits a potent anticancer effect against malignant pleural mesothelioma — Y. Nakajima, T. Kanno, et al. (2015)
• Effects of selected deubiquitinating enzyme inhibitors on the proliferation and motility of lung cancer and mesothelioma cell lines — T. Mirzapoiazova, A. Pozhitkov, et al. (2020)

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