期刊
JOURNAL OF CONTROLLED RELEASE
卷 344, 期 -, 页码 26-38出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2022.02.026
关键词
Peptide-drug conjugate; Prodrug; KRAS mutant cancer; Albumin metabolism; Bystander killing effect; Caspase-3
资金
- Basic Science Research Program through the National Research Foundation of Korea (NRF)
- Ministry of Science, ICT, and Future Planning [2018R1A2A1A05020064]
- Bio & Medical Technology Development Program [2016M3A9B6903384]
- Korean Ministry of Science and ICT (MSIT) [2020R1A2C2015026]
- Korea Drug Development Fund - Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare [HN21C0264]
- BK21 FOUR (Fostering Outstanding Universities for Research) - Ministry of Education (MOE, Korea)
- National Research Foundation of Korea (NRF)
- Korea Evaluation Institute of Industrial Technology (KEIT) [HN21C0264] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2020R1A2C2015026, 2018R1A2A1A05020064] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
This study reports a novel strategy to treat pan-KRAS mutant cancers by utilizing enhanced albumin metabolism to deliver a cytotoxic agent. The researchers found that increased albumin metabolism in KRAS mutant cancer cells induced apoptosis via the uptake of albumin-bound MPD1, resulting in bystander killing of neighboring cancer cells.
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.
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