Oncogenic KRAS Regulates Amino Acid Homeostasis and Asparagine Biosynthesis via ATF4 and Alters Sensitivity to L-Asparaginase

Publication date: 8 January 2018
Source:Cancer Cell, Volume 33, Issue 1
Author(s): Dana M. Gwinn, Alex G. Lee, Marcela Briones-Martin-del-Campo, Crystal S. Conn, David R. Simpson, Anna I. Scott, Anthony Le, Tina M. Cowan, Davide Ruggero, E. Alejandro Sweet-Cordero
KRAS is a regulator of the nutrient stress response in non-small-cell lung cancer (NSCLC). Induction of the ATF4 pathway during nutrient depletion requires AKT and NRF2 downstream of KRAS. The tumor suppressor KEAP1 strongly influences the outcome of activation of this pathway during nutrient stress; loss of KEAP1 in KRAS mutant cells leads to apoptosis. Through ATF4 regulation, KRAS alters amino acid uptake and asparagine biosynthesis. The ATF4 target asparagine synthetase (ASNS) contributes to apoptotic suppression, protein biosynthesis, and mTORC1 activation. Inhibition of AKT suppressed ASNS expression and, combined with depletion of extracellular asparagine, decreased tumor growth. Therefore, KRAS is important for the cellular response to nutrient stress, and ASNS represents a promising therapeutic target in KRAS mutant NSCLC.

Teaser

Gwinn et al. show that oncogenic KRAS regulates amino acid homeostasis and cellular response to nutrient stress via ATF4. They identify ASNS as a key target of the KRAS-ATF4 axis in KRAS-driven non-small-cell lung cancer, revealing a therapeutic vulnerability in asparagine biosynthesis.


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