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Ref Type Journal Article
PMID (38416404)
Authors Pilie PG, Giuliani V, Wang WL, McGrail DJ, Bristow CA, Ngoi NYL, Kyewalabye K, Wani KM, Le H, Campbell E, Sánchez NS, Yang D, Gheeya JS, Goswamy RV, Holla V, Shaw KR, Meric-Bernstam F, Liu CY, Ma X, Feng N, Machado AA, Bardenhagen JP, Vellano CP, Marszalek JR, Rajendra E, Piscitello D, Johnson TI, Likhatcheva M, Elinati E, Majithiya J, Neves J, Grinkevich V, Ranzani M, Roy-Luzarraga M, Boursier M, Armstrong L, Geo L, Lillo G, Tse WY, Lazar AJ, Kopetz SE, Geck Do MK, Lively S, Johnson MG, Robinson HMR, Smith GCM, Carroll CL, Di Francesco ME, Jones P, Heffernan TP, Yap TA
Title Ataxia-Telangiectasia Mutated (ATM) loss of function displays variant and tissue-specific differences across tumor types.
URL
Abstract Text Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed.We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors, and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF biomarker approach in retrospective clinical datasets of patients treated with platinum-based chemotherapy or ATR inhibition.ART0380 had potent, selective anti-tumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10609 ATM variants in 8587 patient tumors. Cancer-lineage specific differences were seen in: the prevalence of deleterious (Tier 1) versus unknown/benign (Tier 2) variants, selective pressure for loss of heterozygosity, and concordance between a deleterious variant and ATM loss of protein (LOP). A novel ATM LOF biomarker approach that accounts for variant classification, relationship to ATM LOP, and tissue-specific penetrance significantly enriched for patients who benefited from platinum-based chemotherapy or ATR inhibition.These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers.

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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
ATM E473* nonsense loss of function - predicted ATM E473* results in a premature truncation of the Atm protein at amino acid 473 of 3056 (UniProt.org). E473* results in the loss of Atm protein expression in patient cells (PMID: 38416404), and due to the effects of other truncation mutations downstream of E473 (PMID: 16603769), is predicted to lead to a loss of Atm protein function.
ATM M779I missense unknown ATM M779I does not lie within any known functional domains of the Atm protein (UniProt.org). M779I has been identified in the scientific literature (PMID: 38416404), but has not been biochemically characterized and therefore, its effect on Atm protein function is unknown (PubMed, Mar 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ATM E473* ATM loss lung adenocarcinoma sensitive ART0380 Preclinical - Pdx Actionable In a preclinical study, ART0380 induced tumor regression in a lung adenocarcinoma patient-derived xenograft (PDX) model harboring ATM E473* with loss of Atm expression (PMID: 38416404). 38416404
ATM S214Ffs*40 ATM loss colorectal cancer sensitive ART0380 Preclinical - Pdx Actionable In a preclinical study, ART0380 inhibited tumor growth in a colorectal cancer patient-derived xenograft (PDX) model harboring ATM S214Ffs*40 with loss of Atm expression (PMID: 38416404). 38416404
ATM M779I colorectal cancer sensitive ART0380 Preclinical - Pdx Actionable In a preclinical study, ART0380 inhibited tumor growth in a colorectal cancer patient-derived xenograft (PDX) model harboring ATM M779I (PMID: 38416404). 38416404
ATM dec exp ATM inact mut mantle cell lymphoma predicted - sensitive ART0380 Preclinical - Cell line xenograft Actionable In a preclinical study, ART0380 inhibited cell growth of a mantle cell lymphoma cell line with an inactivating ATM mutation and decreased Atm expression in culture and inhibited tumor growth in a cell line xenograft model (PMID: 38416404). 38416404
ATM S214Pfs*16 colorectal cancer sensitive ART0380 Preclinical - Pdx Actionable In a preclinical study, ART0380 inhibited tumor growth in a colorectal cancer patient-derived xenograft (PDX) model harboring ATM S214Pfs*16 (PMID: 38416404). 38416404