Macropinocytosis pathway (MP) (MP)

Macropinocytosis is a regulated form of endocytosis where cells internalize large volumes of extracellular fluid and solutes into vesicles called macropinosomes (Commisso et al., 2013, Nature). In cancer cells with oncogenic RAS mutations, such as KRAS-mutant pancreatic and lung cancers, this pathway is constitutively activated to function as a nutrient scavenging mechanism (Finicle et al., 2018, Nature Reviews Cancer). These cells ingest extracellular proteins like albumin and transport them to lysosomes, where they are degraded into amino acids to support tumor metabolism and survival in nutrient-poor environments (Palm, 2019, Trends in Cell Biology). While macropinocytosis is a complex pathway rather than a single molecule, it involves several druggable components including sodium-hydrogen exchangers (NHEs), phosphoinositide 3-kinases (PI3Ks), and p21-activated kinases (PAKs) (Ha et al., 2016, Molecular Cancer Research). Pharmacological targeting of these components, such as with the amiloride derivative EIPA, aims to starve RAS-mutant tumors of essential nutrients. However, therapeutic challenges include the potential for systemic toxicity due to the role of macropinocytosis in normal immune cell function and the ability of cancer cells to adapt via alternative metabolic pathways.

Other names

Bulk-phase endocytosisFluid-phase endocytosisRAS-driven macropinocytosisOncogenic macropinocytosis

Inhibition of sodium-hydrogen exchangers (NHE) to prevent sub-membranous pH changes required for actin remodeling; inhibition of PI3K and PAK1 signaling to disrupt macropinosome formation.