Translational Reprogramming Marks Adaptation to Asparagine Restriction in Cancer

While amino acid restriction remains an attractive strategy for cancer therapy, metabolic adaptations limit its effectiveness. Here we demonstrate a role of translational reprogramming in the survival of asparagine-restricted cancer cells. Asparagine limitation in melanoma and pancreatic cancer cells activates RTK-MAPK as part of a feedforward mechanism involving mTORC1-dependent increase in MNK1 and eIF4E, resulting in enhanced translation of ATF4 mRNA. MAPK inhibition attenuates translational induction of ATF4 and the expression of its target asparagine biosynthesis enzyme ASNS, sensitizing melanoma and pancreatic tumors to asparagine restriction, reflected in their growth inhibition. Correspondingly, low ASNS expression is among the top predictors of response to MAPK signaling inhibitors in melanoma patients and is associated with favorable prognosis, when combined with low MAPK signaling activity. While unveiling a previously unknown axis of adaptation to asparagine deprivation, these studies offer the rationale for clinical evaluation of MAPK inhibitors in combination with asparagine restriction approaches.