Article
作者: Holla, Vijaykumar ; Heffernan, Timothy P ; Shaw, Kenna Rael ; Bristow, Christopher A ; Carroll, Christopher L ; Kopetz, Scott E ; Lillo, Giorgia ; Liu, Chiu-Yi ; Tse, Wai Yiu ; Pilié, Patrick G ; Giuliani, Virginia ; Le, Hung ; Vellano, Christopher P ; Kyewalabye, Keith ; Piscitello, Desiree ; Elinati, Elias ; McGrail, Daniel J ; Wani, Khalida M ; Robinson, Helen M R ; Gheeya, Jinesh S ; Johnson, Timothy I ; Grinkevich, Vera ; Sanchez, Nora S ; Lazar, Alexander J ; Yang, Dong ; Feng, Ningping ; Geo, Lerin ; Johnson, Michael G ; Goswamy, Rohit Vivek ; Majithiya, Jayesh ; Yap, Timothy A ; Armstrong, Lucy ; Ranzani, Marco ; Neves, Joana ; Ngoi, Natalie Y L ; Jones, Philip ; Wang, Wei-Lien ; Geck Do, Mary K ; Rajendra, Eeson ; Lively, Sarah ; Machado, Annette A ; Smith, Graeme C M ; Campbell, Erick ; Ma, XiaoYan ; Boursier, Marie ; Luzarraga, Marina Roy ; Marszalek, Joseph R ; Bardenhagen, Jennifer P ; Di Francesco, M Emilia ; Likhatcheva, Maria ; Meric-Bernstam, Funda
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 data sets of patients treated with platinum-based chemotherapy or ATR inhibition.
RESULTS:ART0380 had potent, selective antitumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10,609 ATM variants in 8,587 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.