1. Academic Validation
  2. 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.
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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