김하린 (서울대학교, Stanford University)

한빛사논문

조회192

서울대학교, Stanford University

J. Control. Release, Jun 20 2024, 372 S0168-3659(24)00376-6 | https://doi.org/10.1016/j.jconrel.2024.06.028 Stimulating macropinocytosis of peptide-drug conjugates through DNA-dependent protein kinase inhibition for treating KRAS-mutant cancer

Ha Rin Kim ^a,b,1, Seong Jin Park ^a,1, Young Seok Cho ^c, Mudhibadhi Knowledge Moyo ^d, Jeong Uk Choi ^e, Na Kyeong Lee ^f, Seung Woo Chung ^g, Seho Kweon ^h, Jooho Park ⁱ, Byoungmo Kim ^a, Yoon Gun Ko^j, Joo Hye Yeo ^k, Jinu Lee ^k, Sang Yoon Kim^l, Youngro Byun^a

^aResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.

^bSchool of Medicine, Stanford University, CA 94305, United States.

^cCollege of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, United States.

^dDepartment of Medicine, Boston University School of Medicine, Boston, MA, 02118, United States.

^eCollege of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea.

^fChemical & Biological Integrative Research Center, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.

^gDepertment of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, United States.

^hDepartment of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Republic of Korea.

ⁱDepartment of Applied Life Science, Konkuk University, Chungju, 27478, Republic of Korea.

^jPharosgen Co.Ltd, Seoul, 05852, Republic of Korea.

^kCollege of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Republic of Korea.

^lDepartment of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.

¹First authors: Ha Rin Kim and Seong Jin Park contributed equally as first authors on this work.

Corresponding author : Youngro Byun

Abstract

KRAS-mutant cancers, due to their protein targeting complexity, present significant therapeutic hurdles. The identification of the macropinocytic phenotype in these cancers has emerged as a promising alternative therapeutic target. Our study introduces MPD1, an macropinocytosis-targeting peptide-drug conjugates (PDC), which is developed to treat KRAS mutant cancers. This PDC is specifically designed to trigger a positive feedback loop through its caspase-3 cleavable characteristic. However, we observe that this loop is hindered by DNA-PK mediated DNA damage repair processes in cancer cells. To counter this impediment, we employ AZD7648, a DNA-PK inhibitor. Interestingly, the combined treatment of MPD1 and AZD7648 resulted in a 100% complete response rate in KRAS-mutant xenograft model. We focus on the synergic mechanism of it. We discover that AZD7648 specifically enhances macropinocytosis in KRAS-mutant cancer cells. Further analysis uncovers a significant correlation between the increase in macropinocytosis and PI3K signaling, driven by AMPK pathways. Also, AZD7648 reinforces the positive feedback loop, leading to escalated apoptosis and enhanced payload accumulation within tumors. AZD7648 possesses broad applications in augmenting nano-sized drug delivery and preventing DNA repair resistance. The promising efficacy and evident synergy underscore the potential of combining MPD1 with AZD7648 as a strategy for treating KRAS-mutant cancers.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-07-10)
연구진국내(교신)+국외 연구진
분야 생명과학 > 노화/암생물학

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