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Ref Type Journal Article
PMID (27625305)
Authors Morgado-Palacin I, Day A, Murga M, Lafarga V, Anton ME, Tubbs A, Chen HT, Ergan A, Anderson R, Bhandoola A, Pike KG, Barlaam B, Cadogan E, Wang X, Pierce AJ, Hubbard C, Armstrong SA, Nussenzweig A, Fernandez-Capetillo O
Title Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML.
Journal Science signaling
Vol 9
Issue 445
Date 2016 Sep 13
URL
Abstract Text Among the various subtypes of acute myeloid leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies because of an attenuated response by p53, a protein that induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AML(MLL) cells (with an MLL-ENL fusion and a constitutively active N-RAS independently of p53. Moreover, ATR inhibition as a single agent exhibited antitumoral activity, both reducing tumor burden after establishment and preventing tumors from growing, in an immunocompetent allograft mouse model of AML(MLL) and in xenografts of a human AML-MLL cell line. We also found that inhibition of ATM, a kinase that senses DNA double-strand breaks, also promoted the survival of the AML(MLL) mice. Collectively, these data indicated that ATR or ATM inhibition represent potential therapeutic strategies for the treatment of AML, especially MLL-driven leukemias.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KMT2A - MLLT1 NRAS G12D acute myeloid leukemia predicted - sensitive AZD0156 Preclinical Actionable In a preclinical study, AZD0156 treatment resulted in growth inhibition of tumor cells and prolonged survival in animal models of acute myeloid leukemia harboring KMT2A-MLLT1 fusion and NRAS G12D (PMID: 27625305). 27625305
KMT2A - MLLT1 NRAS G12D acute myeloid leukemia predicted - sensitive AZ20 Preclinical Actionable In a preclinical study, AZ20 treatment resulted in growth inhibition of tumor cells and prolonged survival in animal models of acute myeloid leukemia harboring KMT2A-MLLT1 fusion and NRAS G12D (PMID: 27625305). 27625305