2. Academic Validation
  3. Ataxia-Telangiectasia Mutated (ATM) loss of function displays variant and tissue-specific differences across tumor types

Ataxia-Telangiectasia Mutated (ATM) loss of function displays variant and tissue-specific differences across tumor types

  • Clin Cancer Res. 2024 Feb 28. doi: 10.1158/1078-0432.CCR-23-1763.
Patrick G Pilie 1,  Virginia Giuliani 1,  Wei-Lien Wang 1,  Daniel J McGrail 2,  Christopher A Bristow 1,  Natalie Y L Ngoi 3,  Keith Kyewalabye 1,  Khalida M Wani 4,  Hung Le 5,  Erick Campbell 6,  Nora S Sánchez 7,  Dong Yang 8,  Jinesh S Gheeya 9,  Rohit Vivek Goswamy 10,  Vijaykumar Holla 11,  Kenna Rael Shaw 1,  Funda Meric-Bernstam 1,  Chiu-Yi Liu 1,  XiaoYan Ma 12,  Ningping Feng 1,  Annette A Machado 1,  Jennifer P Bardenhagen 5,  Christopher P Vellano 1,  Joseph R Marszalek 6,  Eeson Rajendra 13,  Desiree Piscitello 14,  Timothy I Johnson 14,  Maria Likhatcheva 14,  Elias Elinati 13,  Jayesh Majithiya 15,  Joana Neves 14,  Vera Grinkevich 13,  Marco Ranzani 13,  Marina Roy-Luzarraga 14,  Marie Boursier 13,  Lucy Armstrong 13,  Lerin Geo 16,  Giorgia Lillo 17,  Wai Yiu Tse 18,  Alexander J Lazar 1,  Scott E Kopetz 19,  Mary K Geck Do 1,  Sarah Lively 20,  Michael G Johnson 21,  Helen M R Robinson 13,  Graeme C M Smith 15,  Christopher L Carroll 1,  M Emilia Di Francesco 1,  Philip Jones 1,  Timothy P Heffernan 6,  Timothy A Yap 1
Affiliations

Affiliations

  • 1 The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
  • 2 Cleveland Clinic, Cleveland, OH, United States.
  • 3 National University Cancer Institute, Singapore, Singapore, Singapore, Singapore.
  • 4 The University of Texas MD Anderson Cancer Center, Houston, Tx, United States.
  • 5 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.
  • 6 The University of Texas MD Anderson Cancer Center, Houston, United States.
  • 7 LabCorp (United States), Houston, TX, United States.
  • 8 Astellas Pharma, Northbrook, IL, United States.
  • 9 The Ohio State University, Columbus, Ohio, United States.
  • 10 The University of Texas Health Science Center at Houston, United States.
  • 11 Loyola University Chicago, Houston, Tx, United States.
  • 12 MDACC, Houston.
  • 13 Artios Pharma, Cambridge, United Kingdom.
  • 14 Artios Pharma Ltd, Cambridge, United Kingdom.
  • 15 Artios Pharma Limited, Cambridge, United Kingdom.
  • 16 Arios Pharma, Cambridge, United Kingdom.
  • 17 Artios Pharma, cambridge, cambridgshire, United Kingdom.
  • 18 Arios Pharma, United Kingdom.
  • 19 University of Texas MD Anderson Cancer Center, Houston, TX, United States.
  • 20 ChemPartner San Francisco, United States.
  • 21 ChemPartner San Francisco, South San Francisco, United States.
PMID: 38416404 DOI: 10.1158/1078-0432.CCR-23-1763
Abstract

Purpose: 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.

Experimental design: 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.

Results: 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.

Conclusions: 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157941
    ATR激酶抑制剂
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