OA06.03 Transcriptome Analysis of ATM-Deficient NSCLC

Abstract

Current targeted therapy options in lung cancer, such as EGFR and ALK inhibitors, are effective, though limited in use by the low percentage of patients that carry targetable mutations for these biomarkers. Targeting a broader biological process like DNA damage response (DDR), as with recent synthetic lethality exploits in BRCA-deficient tumors, may offer a form of precision therapy for a larger number of patients. We have shown that NSCLC cells deficient in the DDR protein ATM, exhibit similar synthetic lethality when treated with a PARP1 inhibitor, and that NSCLC patients lacking detectable ATM have poorer overall survival. In vitro, ATM deficient, or “ATMic” cells show increased sensitivity to chemotherapeutics at much lower levels when given in combination with PARP inhibitor. This data suggests that ATM status may be an important determinant for treatment modalities including low dose radiation or platin therapy, or novel synthetic lethality therapies. Here, we seek to determine the cause of ATM loss in NSCLC patients through targeted sequencing, and thorough transcriptomic and epigenetic analysis. We perform whole-transcriptome analysis on NSCLC patient samples previously characterized as normal or ATMic, to detect differences in intracellular pathway activation in these tumors. Additional analysis using OncoFinder software identifies possible effective therapies based on which signaling pathways are most active in the normal or ATMic patients. We also perform targeted NGS on these samples. To our knowledge, no sequencing of ATM has been performed on samples that have also been characterized through other methods (i.e. quantitative IHC) to be ATM deficient. We have generated a substantial body of evidence showing that ATM loss has significant impact on the cell sensitivity to several therapeutic modalities. As such ATMic tumors may be treated more effectively using specific treatment strategies than their ATM competent counterparts. Initial analysis of NSCLC cell lines using the outlined methodologies distinguishes ATM status and identifies different therapeutic agents based on inherent molecular differences. A complete analysis of the transcriptome profiles of ATMic NSCLC patients will be presented and discussed. This research helps complete the overall picture of what the therapeutic implications of ATM loss in NSCLC actually are and how ATMic tumors can best be identified in the clinic. Together, these analyses will give us a stronger understanding of the mechanism for ATM loss in NSCLC, as well as allow us to develop an ATMic “signature” for reliably determining ATM status in patients for directing their treatment options.