Oncotarget

Research Papers:

ATM protein is deficient in over 40% of lung adenocarcinomas

Liza C. Villaruz _, Helen Jones, Sanja Dacic, Shira Abberbock, Brenda F. Kurland, Laura P. Stabile, Jill M. Siegfried, Thomas P. Conrads, Neil R. Smith, Mark J. O'Connor, Andrew J. Pierce and Christopher J. Bakkenist

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Oncotarget. 2016; 7:57714-57725. https://doi.org/10.18632/oncotarget.9757

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Abstract

Liza C. Villaruz1,*, Helen Jones2,*, Sanja Dacic3, Shira Abberbock1, Brenda F. Kurland1,4, Laura P. Stabile5, Jill M. Siegfried6, Thomas P. Conrads7, Neil R. Smith2, Mark J. O’Connor2, Andrew J. Pierce2, Christopher J. Bakkenist5,8

1University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

2Astrazeneca, Cambridge, United Kingdom

3Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

4Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA

5Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

6Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA

7Inova Schar Cancer Institute, Inova Center for Personalized Health, Falls Church, VA, USA

8Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

*Co-first authors

Correspondence to:

Christopher J. Bakkenist, email: [email protected]

Keywords: ataxia telangiectasia mutated (ATM), ATM and Rad-3-related (ATR), lung adenocarcinoma, non-small cell lung cancer (NSCLC)

Received: March 21, 2016    Accepted: April 28, 2016    Published: June 01, 2016

ABSTRACT

Lung cancer is the leading cause of cancer-related mortality in the USA and worldwide, and of the estimated 1.2 million new cases of lung cancer diagnosed every year, over 30% are lung adenocarcinomas. The backbone of 1st-line systemic therapy in the metastatic setting, in the absence of an actionable oncogenic driver, is platinum-based chemotherapy. ATM and ATR are DNA damage signaling kinases activated at DNA double-strand breaks (DSBs) and stalled and collapsed replication forks, respectively. ATM protein is lost in a number of cancer cell lines and ATR kinase inhibitors synergize with cisplatin to resolve xenograft models of ATM-deficient lung cancer. We therefore sought to determine the frequency of ATM loss in a tissue microarray (TMA) of lung adenocarcinoma. Here we report the validation of a commercial antibody (ab32420) for the identification of ATM by immunohistochemistry and estimate that 61 of 147 (41%, 95% CI 34%-50%) cases of lung adenocarcinoma are negative for ATM protein expression. As a positive control for ATM staining, nuclear ATM protein was identified in stroma and immune infiltrate in all evaluable cases. ATM loss in lung adenocarcinoma was not associated with overall survival. However, our preclinical findings in ATM-deficient cell lines suggest that ATM could be a predictive biomarker for synergy of an ATR kinase inhibitor with standard-of-care cisplatin. This could improve clinical outcome in 100,000’s of patients with ATM-deficient lung adenocarcinoma every year.


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