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Albumin metabolism targeted peptide-drug conjugate strategy for targeting pan-KRAS mutant cancer.

Abstract
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.
AuthorsYoung Seok Cho, Gui Chul Kim, Hye Min Lee, Byoungmo Kim, Ha Rin Kim, Seung Woo Chung, Hyo Won Chang, Yoon Gun Ko, Yoon Se Lee, Seong Who Kim, Youngro Byun, Sang Yoon Kim
JournalJournal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 344 Pg. 26-38 (04 2022) ISSN: 1873-4995 [Electronic] Netherlands
PMID35202743 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
Chemical References
  • Albumins
  • Antineoplastic Agents
  • KRAS protein, human
  • Peptides
  • Proto-Oncogene Proteins p21(ras)
Topics
  • Albumins
  • Animals
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Cell Line, Tumor
  • Humans
  • Mice
  • Mutation
  • Neoplasms (drug therapy)
  • Peptides
  • Proto-Oncogene Proteins p21(ras) (genetics)
  • Xenograft Model Antitumor Assays

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