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    1m
    Transcriptome-wide gene expression outlier analysis pinpoints therapeutic vulnerabilities in colorectal cancer. (PubMed, Mol Oncol)
    As a proof of concept, we found that CRC cell lines lacking expression of the MTAP gene are sensitive to treatment with a PRMT5-MTA inhibitor (MRTX1719). Finally, other tumor types may also benefit from this approach.
    Journal
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    MTAP (Methylthioadenosine Phosphorylase)
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    MRTX1719
    6ms
    Early Clinical Success of MTA-Cooperative PRMT5 Inhibitors for the Treatment of CDKN2A/MTAP-Deleted Cancers. (PubMed, Cancer Discov)
    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).
    Journal
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    CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MTAP (Methylthioadenosine Phosphorylase)
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    CDKN2A deletion • MTAP deletion
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    MRTX1719
    6ms
    MRTX1719 is an MTA-cooperative PRMT5 inhibitor that exhibits synthetic lethality in preclinical models and patients with MTAP deleted cancer. (PubMed, Cancer Discov)
    MRTX1719 demonstrated marked anti-tumor 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 MPNST from the Phase 1/2 study.
    Preclinical • Clinical Trial,Phase II • Journal • Synthetic lethality
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    MTAP (Methylthioadenosine Phosphorylase)
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    MTAP deletion
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    MRTX1719
    7ms
    Phase 1/2 Study of MRTX1719 in Solid Tumors With MTAP Deletion (clinicaltrials.gov)
    P1/2, N=370, Recruiting, Mirati Therapeutics Inc. | Trial completion date: Jan 2024 --> Apr 2026 | Trial primary completion date: Jan 2024 --> Apr 2026
    Trial completion date • Trial primary completion date • Metastases
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    MTAP (Methylthioadenosine Phosphorylase)
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    MRTX1719
    1year
    Identification of mechanism-based combination targets effective with the MTA-cooperative PRMT5 inhibitor MRTX1719 for the treatment of MTAP deleted cancers (AACR 2023)
    Prioritized strategies were tested in vivo where MRTX1719, in combination with agents inhibiting complementary mechanisms of action, demonstrated enhanced tumor growth inhibition compared to either agent alone, including but not limited to palbociclib (CDK4/6), olaparib (PARP), and Type I PRMT and Bcl-xL inhibitors. Further investigation into potential biomarkers conferring sensitivity or resistance to PRMT5 inhibition was also performed using orthogonal datasets including molecular characterization, differential expression, differential splicing and proteomic analysis. These data suggest MRTX1719, an MTA cooperative PRMT5 inhibitor currently in a Phase I clinical trial (NCT05245500), has the potential to be a synthetically lethal precision medicine for multiple indications harboring MTAP del with high unmet medical need either as a single agent or in combination with clinically feasible rational combination partners.
    PARP Biomarker
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    CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MTAP (Methylthioadenosine Phosphorylase) • CDK4 (Cyclin-dependent kinase 4) • BCL2L1 (BCL2-like 1) • PRMT5 (Protein Arginine Methyltransferase 5)
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    CDKN2A deletion • MTAP deletion
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    Lynparza (olaparib) • Ibrance (palbociclib) • MRTX1719
    2years
    Phase 1/2 Study of MRTX1719 in Solid Tumors With MTAP Deletion (clinicaltrials.gov)
    P1/2, N=339, Recruiting, Mirati Therapeutics Inc. | Initiation date: Feb 2022 --> May 2022
    Trial initiation date
    |
    MTAP (Methylthioadenosine Phosphorylase)
    |
    MRTX1719
    2years
    Phase 1/2 Study of MRTX1719 in Solid Tumors With MTAP Deletion (clinicaltrials.gov)
    P1/2, N=339, Recruiting, Mirati Therapeutics Inc.
    New P1/2 trial
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    MTAP (Methylthioadenosine Phosphorylase)
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    MRTX1719