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Macropinocytosis-targeted peptide-docetaxel conjugate for bystander pancreatic cancer treatment
Young Seok Cho1, Hanhee Cho2, Ha Rin Kim3
1Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul 08826, Republic of Korea; Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Abstract:
Oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are highly prevalent in pancreatic ductal adenocarcinoma (PDAC) and have garnered attention as potential targets for targeted therapies, such as KRAS inhibitors. However, the limited therapeutic efficacy of KRAS allele-specific inhibitors necessitate an efficient pan-KRAS cancer cell killing strategy. Here, we have examined enhanced macropinocytosis pathway in KRAS mutant cancer cells and report improved intracellular delivery of albumin-based therapeutics. We further established an albumin-binding peptide-docetaxel conjugate platform (MPD3), which has a caspase-3 cleavable feature, for macropinocytosis-targeted bystander payload delivery and realization of bystander killing of pan-KRAS cancer cells, complemented with caspase-3 mediated activation of MPD3 to bolster tumoral accumulation of cytotoxic payloads. Utilization of in vitro co-culture system of pan-KRAS cancer cells and pharmacodynamic marker staining revealed potent bystander killing effects of MPD3, highlighting MPD3 as an efficient delivery platform against pan-KRAS cancer. Moreover, MPD3 elicited robust anti-tumor activities in both local and liver metastatic PDAC tumor models in mice. Overall, this work establishes a paradigm for developing translational pan-KRAS cancer treatment and broadens the applicability of albumin binding peptide-drug conjugate against albumin-metabolism enriched cancers.
Insights
Researchers developed MPD3, an albumin-binding peptide-docetaxel conjugate, to target KRAS-mutant pancreatic cancer cells. This strategy enhances drug delivery via macropinocytosis, leading to effective bystander killing and significant anti-tumor activity in preclinical models.
Area of Science:
- Oncology
- Drug Delivery
- Molecular Biology
Background:
- KRAS mutations are common in pancreatic ductal adenocarcinoma (PDAC).
- Current KRAS inhibitors have limited efficacy, necessitating new pan-KRAS strategies.
- Macropinocytosis is enhanced in KRAS-mutant cancer cells.
Purpose of the Study:
- To develop an efficient strategy for pan-KRAS cancer cell killing.
- To improve intracellular delivery of albumin-based therapeutics in KRAS-mutant cells.
- To establish a novel drug delivery platform targeting KRAS-mutant cancers.
Main Methods:
- Examined enhanced macropinocytosis in KRAS-mutant cancer cells.
- Developed an albumin-binding peptide-docetaxel conjugate (MPD3) with caspase-3 cleavage.
- Utilized in vitro co-culture systems and in vivo mouse models (PDAC).
Main Results:
- MPD3 demonstrated improved intracellular delivery and bystander killing of pan-KRAS cancer cells.
- Caspase-3 mediated activation of MPD3 enhanced cytotoxic payload accumulation.
- MPD3 showed potent anti-tumor activity in local and metastatic PDAC models.
Conclusions:
- MPD3 is an efficient delivery platform for targeting pan-KRAS cancers.
- This approach establishes a paradigm for translational pan-KRAS cancer treatment.
- Albumin-binding peptide-drug conjugates show broad applicability in albumin-metabolism enriched cancers.
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