Perlmutter Cancer Center, NYU School of Medicine
Cancer is a multistep process that involves alterations in cell-autonomous and non-cell autonomous events that are modulated by metabolic factors. My laboratory uses genetically engineered mouse models (GEMMs) of lung cancer, which recapitulate the genetics, histological progression and tissue microenvironment, to elucidate the interactions of tumor intrinsic oncogenic events with systemic changes in physiology, diet and metabolism during tumor progression (Papagiannakopoulos et al, Cell Metabolism, 2016). Using CRISPR/Cas9-based genome engineering in both mouse models and human pre-clinical models, we have developed a platform to rapidly characterize the function of clinically relevant lung cancer mutations, elucidate their mechanism of action and identify novel targeted therapies against complex genetic subtypes of lung cancer (Sánchez-Rivera and Papagiannakopoulos, et al, Nature, 2014; Romero et al., Nature Medicine, 2017). Since the establishment of our laboratory, we have made significant progress in applying our approaches to characterize a major genetic subset of lung adenocarcinoma with NRF2/KEAP1 mutations, a lung cancer type with great clinical need. Patients with KEAP1/NRF2 mutations have the worst prognosis of all lung cancer patients and do not respond well to standard of care chemotherapy and/or immunotherapy. Leveraging our unique expertise in lung cancer, genome engineering and metabolism, we are investigating how NRF2/KEAP1 mutations promote lung cancer by reprogramming cellular metabolism during tumor progression. We have demonstrated the therapeutic potential of targeting metabolism in highly relevant pre-clinical mouse and human lung cancer models (Ashouri et al., Nat. Comm, 2017; Romero et al., Nature Medicine, 2017; Sayin et al., eLife, 2017; Lignitto et al., Cell, 2019; Leboeuf et al., Cell Metabolism, 2019). Our studies have led to multiple phase 2 trials with glutamine-based therapies in lung cancer patients genetically stratified patients by NRF2/KEAP1 mutations. Our group is currently investigating the mechanisms underlying novel metabolic dependencies in multiple genetic subsets of lung cancer, including STK11/LKB1 mutant lung adenocarcinoma.