2. Academic Validation
  3. Albumin metabolism targeted peptide-drug conjugate strategy for targeting pan-KRAS mutant cancer

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

  • J Control Release. 2022 Apr;344:26-38. doi: 10.1016/j.jconrel.2022.02.026.
Young Seok Cho 1,  Gui Chul Kim 2,  Hye Min Lee 2,  Byoungmo Kim 3,  Ha Rin Kim 3,  Seung Woo Chung 4,  Hyo Won Chang 2,  Yoon Gun Ko 5,  Yoon Se Lee 2,  Seong Who Kim 6,  Youngro Byun 7,  Sang Yoon Kim 8
Affiliations

Affiliations

  • 1 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul 08826, Republic of Korea.
  • 2 Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
  • 3 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
  • 4 Center for Nanomedicine, Wilmer Eye Institute and Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA, Seoul 08826, Republic of Korea.
  • 5 Pharosgen Co.Ltd, 2-404 Jangji-dong 892, Seoul 05852, Republic of Korea.
  • 6 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
  • 7 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: yrbyun@snu.ac.kr.
  • 8 Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea. Electronic address: sykim2@amc.seoul.kr.
PMID: 35202743 DOI: 10.1016/j.jconrel.2022.02.026
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.

Keywords

Albumin metabolism; Bystander killing effect; Caspase-3; KRAS mutant cancer; Peptide-drug conjugate; Prodrug.

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