MAPK/p38-ULK1-PI4KB signaling defines a non-canonical autophagy mechanism in KRAS-Mutant tumors

Although KRAS-driven tumors exhibit elevated macroautophagy/autophagy, the extent to which this process diverges from canonical regulatory pathways has not been well characterized. In a recent study published in Cell Research, Wang et al. unveil a novel form of non-canonical autophagy driven by oncogenic RAS mutations, which they termed RAS-induced non-canonical autophagy via ATG8ylation (RINCAA). This pathway operates through a unique MAPK/p38-ULK1-PI4KB axis, diverging significantly from canonical starvation-induced autophagy. The research not only elucidates a new regulatory mechanism but also identifies a potential, highly specific therapeutic target for RAS-mutant cancers.<b>Abbreviations</b>: PI4KB, phosphatidylinositol 4-kinase beta; PtdIns4P, phosphatidylinositol-4-phosphate; RINCAA, RAS-induced non-canonical autophagy via Atg8ylation; ULK1, unc-51 like autophagy activating kinase 1; WIPI2, WD repeat domain phosphoinositide-interacting protein 2.