KRAS (mutant; tumor-selective delivery via macropinocytosis) with a

Class

Non-antibody protein/peptide-drug conjugate exploiting RAS-driven macropinocytosis for tumor-selective payload delivery

Pathway

RAS-driven macropinocytotic uptake; microtubule disruption

Notes

original target text: KRAS (mutant; tumor-selective delivery via macropinocytosis) with a tubulin-targeting cytotoxic payload

KRAS is a small GTPase that normally cycles between active and inactive states to relay growth-factor signaling into the cell. Mutations that occur in a substantial fraction of cancers lock the protein in its active form, producing continuous proliferative signaling and reshaping broader aspects of cell physiology, including how cells acquire nutrients. One consequence of this altered signaling is heightened macropinocytosis, a bulk, non-selective process in which cells engulf large volumes of extracellular fluid and its dissolved contents. Tumor cells with active RAS signaling appear to rely on this route to scavenge nutrients when proliferative demands outpace conventional uptake mechanisms. This mechanism exploits that biology for drug delivery: instead of directly targeting mutant KRAS itself, a construct carrying a cytotoxic payload is designed to be internalized preferentially through macropinocytosis, concentrating drug exposure in cells with elevated uptake activity. The payload is a tubulin-targeting cytotoxic agent, a class of compound that disrupts microtubule function, halting cell division and promoting cell death. This strategy is relevant across the broad group of cancers driven by mutant KRAS, and it offers a route to tumor selectivity that does not depend on a molecule capable of binding and inhibiting the mutant RAS protein directly.