Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis

Nature Medicine 23, 1362 (2017). doi:10.1038/nm.4407 Authors: Rodrigo Romero, Volkan I Sayin, Shawn M Davidson, Matthew R Bauer, Simranjit X Singh, Sarah E LeBoeuf, Triantafyllia R Karakousi, Donald C Ellis, Arjun Bhutkar, Francisco J Sánchez-Rivera, Lakshmipriya Subbaraj, Britney Martinez, Roderick T Bronson, Justin R Prigge, Edward E Schmidt, Craig J Thomas, Chandra Goparaju, Angela Davies, Igor Dolgalev, Adriana Heguy, Viola Allaj, John T Poirier, Andre L Moreira, Charles M Rudin, Harvey I Pass, Matthew G Vander Heiden, Tyler Jacks & Thales Papagiannakopoulos Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein. One approach to addressing this challenge is to define mutations that frequently co-occur with those in KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function mutations in the KEAP1 gene encoding Kelch-like ECH-associated protein 1 (refs. 2, 3, 4), a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response. The high frequency of mutations in KEAP1 suggests an important role for the oxidative stress response in lung tumorigenesis. Using a CRISPR–Cas9-based approach in a mouse model of KRAS-driven LUAD, we examined the effects of Ke...
Source: Nature Medicine - Category: General Medicine Authors: Tags: Letter Source Type: research