Seminar: "Dissecting the role of the endogenous antioxidant response in lung cancer"
Title: "Dissecting the role of the endogenous antioxidant response in lung cancer"
Speaker: Dr. Volkan Sayin, New York University
The talk is based on two recently accepted papers (Nat. Med. and eLIFE).
Targeting KRAS-mutant lung cancer remains a major clinical challenge. Genetic and metabolic diversity among KRAS-mutant cancers might underlie the limited success of synthetic lethal targets in translational oncology. Here we combined a mouse model of KRAS-driven lung cancer with the CRISPR/Cas9 system to functionally characterize the Keap1/Nrf2 antioxidant pathway, which is mutated in 20-30% of lung cancers. We show that somatic editing of Keap1/Nrf2 accelerates lung cancer progression through hyper-activation of the Nrf2–antioxidant pathway.
Combining metabolomics and focused genetic screening, we uncover that Keap1/Nrf2 mutant cancers are metabolically rewired to depend on glutaminolysis. We demonstrate that this dependence can be therapeutically exploited in both patient derived xenograft and autochthones mouse models of lung cancer through CB-839, a glutaminase inhibitor currently in phase I clinical-trials. Furthermore, we show that cancers beyond Keap1/Nrf2 mutants can become metabolically rewired to depend on glutaminolysis and identify potential resistance mechanisms. Our studies define Keap1 as a bona-fide tumor suppressor in KRAS-driven lung cancer. Furthermore, we provide a rationale for sub-stratification of Kras-Keap1/Nrf2 mutant lung cancer patients as likely responders to glutaminase inhibitors.
Host: Martin Bergö, Dept. of Biosciences and Nutrition, firstname.lastname@example.orgContact person: Martin Bergö