Despite recent breakthroughs in the development of direct KRAS inhibitors and modulators, no drugs targeting pan-KRAS mutant
cancers are clinically available. Here, we report a novel strategy to treat pan-KRAS
cancers using a
caspase-3 cleavable
peptide-drug conjugate that exploits enhanced
albumin metabolism in KRAS altered
cancers to deliver a
cytotoxic agent that can induce a widespread bystander killing effect in
tumor cells. Increased
albumin metabolism in KRAS mutant
cancer cells induced apoptosis via the intracellular uptake of
albumin-bound MPD1. This allowed
caspase-3 upregulation activated MPD1 to release the payload and exert the non-selective killing of neighboring
cancer cells. MPD1 exhibited potent and durable antitumor efficacy in mouse xenograft models with different KRAS genotypes. An augmentation of anti-
cancer efficacy was achieved by the bystander killing effect derived from the
caspase-3 mediated activation of MPD1. In summary,
albumin metabolism-induced apoptosis, together with the bystander killing effect of MPD1 boosted by
caspase-3 mediated activation, intensified the efficacy of MPD1 in KRAS mutant
cancers. These findings suggest that this novel
peptide-drug conjugate could be a promising breakthrough for the treatment in the targeting of pan-KRAS mutant
cancers.