Rationale: Lung cancers are often discovered at advanced stages after they have escaped their primary sites and traveled to distant locations throughout the body. When this happens, patients must be treated with systemic therapies that can often reduce, but rarely fully eradicate, the disease. The tumor cells that survive therapy – termed “residual” cells – ultimately grow, leading to relapse, therapeutic resistance, and death. For this reason, we and others are focusing our work on residual tumor cells in an effort to define their properties and, ultimately, therapeutic strategies that can be used to eliminate them. In this proposal, we describe our recent, surprising discovery that residual lung tumor cells that survive treatment with first-line, approved, and emerging targeted therapies exhibit a unique and actionable property: DNA damage. Our studies taught us that this DNA damage is caused by residual cells’ exposure to targeted therapy. Thus, although therapy does not kill these cells, the persistent DNA damage it causes means that residual tumor cells must persistently activate DNA damage repair processes in order to survive. We further discovered that this necessary DNA repair is controlled by an enzyme called ATM, and that blocking ATM function with drugs leads to the eradication of residual tumor cells and improved long-term treatment responses in cellular and animal models of lung cancer. These findings are backed up by clinical observations: residual tumors from patients show marked elevation of ATM function, and rare patients whose tumors harbor ATM mutations that block its function exhibit much more durable responses to therapy. Here, we propose to build on these findings by defining the optimal clinical settings for advancing ATM inhibitors as combination therapies to improve the depth and duration of responses to existing, approved targeted therapy drugs. By defining and evaluating an actionable, mechanism-based vulnerability of residual lung tumors, this work will address three LCRP Areas of Emphasis: (1) identify innovative strategies for the treatment of lung cancer; (2) identify innovative strategies for the prevention of recurrence of or metastases from lung cancer; and (3) understand mechanisms of resistance to treatment (primary and secondary).

Objective/Aims: To maximize and accelerate the near-term translational potential of this discovery, we have assembled a team of world-leading lung cancer clinicians and biologists from academia and the Department of Veterans Affairs hospital system who will work together to examine two key aims, then leverage the lessons we learn to drive the design and execution of near-term clinical trials. In Aim 1, we will use “gold standard” mouse models of patient-derived EGFR mutant lung cancer to examine the impact of EGFR inhibitor + ATM inhibitor combination therapies in both the upfront and progressive disease settings. In Aim 2, we will evaluate the extent to which our findings can be extended to additional, diverse, genetically defined subsets of lung cancer. Both aims will be supplemented by deep mechanistic and correlative analyses to connect our findings with both underlying molecular mechanisms and their clinical implications for human patients.

Applicability: This work has the potential to lead to new, improved therapeutic strategies that could yield more robust, long-term responses to therapy in patients with advanced lung cancers. The first clinical implications of this work will likely be felt before the funding period is complete, when the results of the first half of our studies in the EGFR mutant lung cancer setting define optimal pathways forward into clinical trials. The second half of our studies promise to similarly yield near-term (2-4 year) clinical impact by defining how to best position ATM inhibitors in other subsets of lung cancer. More broadly, by defining novel and critical biological mechanisms that exist in residual tumors, this work will spur additional basic and eventually translational research that will further take advantage of this knowledge. Together, by revealing mechanism-based strategies for targeting residual lung cancer, these studies have the potential to improve the health of the many military, Veteran, and civilian patients fighting this particularly aggressive and deadly malignancy.