Abstract PR14: MEK inhibitors block growth of Ataxia Telangiectasia Mutated (ATM) mutant lung tumors

Introduction: Lung cancer is the leading cause of cancer death worldwide. In the past decade, deep sequencing projects have shed light on the molecular drivers commonly found altered in NSCLC. As a result, the first molecularly targeted agents have been approved for the treatment of tumors presenting activating oncogenic events in EGFR or EML4/ALK. However, the translation into therapies for tumors presenting loss-of-function mutations has proven challenging and constitutes an unexplored and promising field. In order to narrow the gap between cancer genomics and effective treatments for tumors harboring mutations in well-defined tumor suppressor genes (such as PTEN, BRG1 or ATM), we have developed a genetically tractable lung cancer cell model. Focusing on lung adenocarcinoma, we have engineered a panel of isogenic cell lines capturing the molecular heterogeneity found in patients. This panel has been screened against a collection of drugs, comprising classical chemotherapeutics and kinase inhibitors, providing a comprehensive evaluation for hundreds of gene-drug interactions. Results: The screen confirmed known or highly expected interactions, proving the robustness of our approach. Among the unexpected and most relevant hits, we have found that ATM-deficient cells are exquisitely sensitive to drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Extensive validation in ATM mutant patient-derived lung cancer cell lines has confirmed the synthetic lethal interaction between ATM and MEK in vitro and in vivo. Mechanistically, the interaction may not be directly associated with the major role of ATM in DNA damage signaling. Rather, we have observed a deregulation of the crosstalk between the MAPK and AKT/mTOR signaling pathways as a consequence of ATM deficiency, resulting in an increased dependency on MEK kinase activity for cell survival. Perspectives: Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma (5- 10%) but directly targeting these with drugs remains challenging. MEK inhibitors are currently being tested in clinical trials for efficacy in KRAS or BRAF mutant lung cancer. However, these mutations alone do not adequately predict response to MEK inhibition. Our findings indicate that including ATM mutation status in lung cancer as a mechanistic biomarker for MEK inhibitors can improve patient stratification. Ultimately, extending the applicability of these drugs beyond KRAS or BRAF mutant tumors. Citation Format: Ferran Fece de la Cruz, Michal Smida, Sebastian Nijman. MEK inhibitors block growth of Ataxia Telangiectasia Mutated (ATM) mutant lung tumors [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr PR14.