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Data from Ataxia-Telangiectasia Mutated Loss-of-Function Displays Variant and Tissue-Specific Differences across Tumor Types

Posted on 2024-05-15 - 07:23
AbstractPurpose:

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.

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FUNDING

National Cancer Institute (NCI)

United States Department of Health and Human Services

Cancer Prevention and Research Institute of Texas (CPRIT)

Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (Khalifa Institute)

U.S. Department of Defense (DOD)

V Foundation for Cancer Research (VFCR)

Conquer Cancer Foundation (CCF)

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AUTHORS (51)

Patrick G. Pilié
Virginia Giuliani
Wei-Lien Wang
Daniel J. McGrail
Christopher A. Bristow
Natalie Y.L. Ngoi
Keith Kyewalabye
Khalida M. Wani
Hung Le
Erick Campbell
Nora S. Sanchez
Dong Yang
Jinesh S. Gheeya
Rohit Vivek Goswamy
Vijaykumar Holla
Kenna Rael Shaw
Funda Meric-Bernstam
Chiu-Yi Liu
XiaoYan Ma
Ningping Feng
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