Metabolic Mechanisms of Lung Cancer Progression

KRAS mutant lung adenocarcinoma is the major form of lung cancer that remains a major challenge for clinical oncology because patients are refractory to standard-of-care. KRAS mutant tumors display a high degree of genetic heterogeneity and emerging clinical data suggest that specific KRAS co-mutations are associated with poor prognosis and failure of cancer therapies. Our group uses genetically engineered mouse models and patient samples to dissect how genetic subsets of KRAS mutant lung cancer promote tumorigenesis by rewiring cancer cell metabolism, promoting immune evasion and therefore contributing to tumor progression and therapy resistance. We have identified novel therapeutic approaches to both suppress tumor metabolism and reverse the immunosuppressive microenvironment of genetic subsets of KRAS-driven lung cancer.

Furthermore, accumulating evidence indicates that oxidative stress can lead to excessive lipid peroxidation, membrane rupture and subsequently cell death by ferroptosis. Although many mechanisms have been found to regulate ferroptosis in vitro, there is limited understanding whether ferroptosis is a barrier tumor cells have to overcome during tumorigenesis. Using KRAS-driven preclinical models we demonstrate that tumors have to buffer against lipid peroxidation and that genetic or pharmacological targeting of a major ferroptosis suppressing pathway can trigger ferroptosis and suppress tumor growth.

 

1. Pillai R*, LeBoeuf SE*, Hao Y, New C, Blum JLE, Rashidfarrokhi A, Huang SM, Bahamon C, Wu WL, Karadal-Ferrena B, Herrera A, Ivanova E, Cross M, Bossowski JP, Ding H, Hayashi M, Rajalingam S, Karakousi T, Sayin VI, Khanna KM, Wong KK, Wild R, Tsirigos A, Poirier JT, Rudin CM, Davidson SM, Koralov SB, Papagiannakopoulos T. Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer. Sci Adv. 2024 Mar 29;10(13):eadm9859. doi: 10.1126/sciadv.adm9859.PMID: 38536921

2. LeBoeuf SE*, Wu WL*, Karakousi TR, Karadal B, Jackson SR, Davidson SM, Wong KK, Koralov SB, Sayin VI, Papagiannakopoulos T. Activation of Oxidative Stress Response in Cancer Generates a Druggable Dependency on Exogenous Non-essential Amino Acids. Cell Metabolism. 2019 Nov 28. pii: S1550-4131(19)30619-9. doi: 10.1016/j.cmet.2019.11.012. print. PMID: 34344

3. Lignitto L; LeBoeuf SE; Homer H; Jiang S; Askenazi M; Karakousi TR; Pass HI; Bhutkar AJ; Tsirigos A; Ueberheide B; Papagiannakopoulos T.#, Pagano M.# Nrf2 activation promotes lung cancer metastasis by blocking degradation of Bach1. Cell. 2019 Jul 11;178(2):316-329.e18. doi: 10.1016/j.cell.2019.06.003.

4. Romero R*, Sayin VI*; Davidson SM; Bauer MR; Singh SX; LeBoeuf SE; Karakousi TR; Ellis DC; Bhutkar A; Sánchez-Rivera FJ; Subbaraj L; Martinez B; Bronson RT; Prigge JR; Schmidt EE; Thomas CJ; Goparaju C; Davies A; Dolgalev I; Heguy A; Allaj V; Poirier JT; Moreira AL; Rudin CM; Pass HI; Vander Heiden MG; Jacks T#; Papagiannakopoulos T#. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat Med. (2017).

5. Sayin VI*; LeBoeuf SE*; Singh SX; Davidson SM; Biancur D; Guzelhan BS; Alvarez SW; Wu WL; Karakousi TR; Zavitsanou AM; Ubriaco J; Muir A; Karagiannis D; Morris PJ; Thomas CJ; Possemato R, Vander Heiden MG; Papagiannakopoulos T. Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer. Elife. (2017).