Rationale: Lung cancer is the leading cause of cancer mortality in the world, responsible for more deaths than colon, breast, and prostate cancers combined. Our preliminary data from over 1,000 patients with lung adenocarcinoma (LUAD) indicates that tumors with concurrent mutations in two genes (LKB1 and KEAP1) comprise about 10% of all LUAD and predicts a rapid and lethal disease course that is resistant to current therapies. Therefore, we conducted preclinical experiments to characterize cells possessing these mutations, finding that LKB1/KEAP1 co-mutation dramatically enhances the cancer-causing attributes of these cells compared to wild-type or cells possessing only one of these mutations. Subsequent experiments found that cells possessing both LKB1/KEAP1 mutations are particularly adept at avoiding a type of cell death called ferroptosis. The role of ferroptosis has not been previously explored in LKB1/KEAP1 co-mutant LUAD. This proposal seeks to fill this void with an eye toward using currently available inducers of ferroptosis to overcome the aggressive nature of LKB1/KEAP1 co-mutant LUAD and improve outcomes in patients with this type of cancer.

LCRP Areas of Emphasis: (1) Identify innovative strategies for the treatment of lung cancer and (2) develop or optimize predictive markers to assist with therapeutic decision-making.

Applicability of Research: This line of research has the potential to profoundly impact patients with LKB1/KEAP1 co-mutant LUAD, as well as other cancer types (like renal, breast, pancreatic, ovarian cancers) that rely on evasion of ferroptosis for their survival. Our research has been optimized for rapid translation in several ways. First, we have focused on pathways with small-molecule inhibitors that are already established and are often approved or in clinical trials for other diseases. Second, we are leveraging the resources of Memorial Sloan Kettering Cancer Center (MSK) by extending and validating our preclinical findings in clinical samples. Not only does this approach strengthen the scientific rigor of our proposal, it also paves the way for translating our findings into clinical trials that can be up and running in months as opposed to years – a model that we have successfully applied in other cancer subsets.

Finally, co-investigator, Dr. Charles Rudin is a world-renowned clinical and basic-science researcher in the area of lung cancer with the capacity to lead clinical trials that grow out of the preclinical studies this proposal is likely to generate. MSK is a leader in the development of cancer treatments and has aligned its research infrastructure to smooth the adaptation of basic science findings into clinical trials. The ability to target genetic anomalies in other cancer subsets has increased survival from months to years. For patients with LKB1/KEAP1 co-mutant LUAD, median survival is just 7.3 months, so the benefits of identifying a tailored treatment are potentially vast. As such, the risks for patients are minimal; some may not respond to treatment and others may suffer minor or major side effects. These risks are mitigated by the potential to stave off death.

Contributions to Lung Cancer Research: Our proposal explores the role of a novel pathway in lung cancer research, ferroptosis, and explores an overlooked population of patients, those with LKB1/KEAP1 co-mutant LUAD. We anticipate clinical application of our research within the tenure of the current applications (2 years). Our experiments are designed to optimally characterize this patient subset so that even if our original hypothesis isn’t supported, future studies will have ample data to mine in search of other treatment targets for these patients. If our hypothesis is supported, then the treatment paradigm for patients with LKB1/KEAP1 co-mutant LUAD could be revolutionized and outcomes substantially improved.

Military Relevance: As in other diseases, lung cancer is enriched in military Service members and Veterans. Although our study will include patient samples from any patient at MSK, many of the patients we treat are Veterans. More importantly, the findings from our study will be applicable to all patients with LKB1/KEAP1 co-mutant LUAD and, more generally, to cancers that evade ferroptosis as a primary mechanism of growth. Treatments for patients with LKB1/KEAP1 co-mutant LUAD are limited and ineffective, so new therapeutic options such as those we explore in this proposal are urgently needed.