biostudies-literaturePilie PGSheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer TherapyCancer Prevention and Research Institute of Texas (CPRIT)Conquer Cancer Foundation (CCF)U.S. Department of Defense (DOD)V Foundation for Cancer Research (VFCR)Cancer Prevention and Research Institute of TexasNational Cancer Institute (NCI)Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (Khalifa Institute)U.S. Department of DefenseNational Cancer InstituteNCI NIH HHSConquer Cancer FoundationV Foundation for Cancer Research2121-2139https://www.ebi.ac.uk/biostudies/studies/S-EPMC11094420biostudies-literatureUnknown30(10)<h4>Purpose</h4>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.<h4>Experimental design</h4>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 data sets of patients treated with platinum-based chemotherapClinical cancer research : an official journal of the American Association for Cancer ResearchAtaxia-Telangiectasia Mutated Loss-of-Function Displays Variant and Tissue-Specific Differences across Tumor Types.PMC11094420P30 CA016672RP150535R01 CA255074VC2020-001R01-CA255074OC200482Kyewalabye KArmstrong LBoursier MGeo LJohnson MGSmith GCMKopetz SEGiuliani VShaw KRGoswamy RVMeric-Bernstam FLe HVellano CPYang DYap TAElinati EFeng NGrinkevich VLiu CYJones PMachado AACarroll CLWani KMGeck Do MKLazar AJLikhatcheva MTse WYMa XBristow CANgoi NYLSanchez NSMajithiya JPiscitello DMarszalek JRGheeya JSDi Francesco MEHolla VLuzarraga MRRobinson HMRMcGrail DJPilie PGRajendra EBardenhagen JPLively SRanzani MLillo GWang WLCampbell EJohnson TIHeffernan TPNeves JfalseAtaxia-Telangiectasia Mutated Loss-of-Function Displays Variant and Tissue-Specific Differences across Tumor Types.<h4>Purpose</h4>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.<h4>Experimental design</h4>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 data sets of patients treated with platinum-based chemotherap2024-01-01T00:00:00Z2024 May2026-06-02T08:17:53.994Z2026-05-26T03:07:25.553ZS-EPMC110944203841640410.1158/1078-0432.CCR-23-1763