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Exploiting macropinocytosis for drug delivery into KRAS mutant cancer
1School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, and Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, P.R. China.
Abstract:
KRAS mutations are one of the most common gene mutations linked to cancer, presenting in approximately 25% of all tumors, especially pancreatic, lung, and colorectal cancers. Mutant KRAS has long been considered an undruggable target, stalling progress in direct KRAS targeting for many years, while targeted drug delivery into KRAS mutant cells utilizing their transformed metabolic behavior might present an alternative opportunity. Macropinocytosis, a nonselective, fluid-phase, endocytic route, was found to be upregulated as a metabolic feature in KRAS-driven tumors and plays a critical role in nutrient acquisition from extracellular fluids. With the observation that a variety of drug delivery systems could be internalized by KRAS mutant cancer cells through macropinocytosis, exploiting macropinocytosis for intracellular delivery of therapeutics into KRAS mutant tumor cells is emerging as a new drug delivery expedition. In this article, we summarized cancer biology studies that examined KRAS mutation-induced macropinocytosis, reviewed recent studies exploiting macropinocytosis enhancement for KRAS mutant cancer cell-selective drug delivery, and discussed the potential opportunities, challenges and pitfalls of this strategy.
Insights
Targeting KRAS-mutant cancers may be possible by exploiting macropinocytosis, a cellular process upregulated in these tumors. This approach uses drug delivery systems to target KRAS-mutant cells, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Delivery
Background:
- KRAS mutations are prevalent in ~25% of cancers, including pancreatic, lung, and colorectal.
- Mutant KRAS has been historically challenging to target directly with therapies.
- KRAS-driven tumors exhibit upregulated macropinocytosis, a cellular uptake mechanism.
Purpose of the Study:
- To summarize research on KRAS mutation-induced macropinocytosis.
- To review strategies for enhancing macropinocytosis for targeted drug delivery in KRAS-mutant cancers.
- To discuss the potential and challenges of this drug delivery approach.
Main Methods:
- Literature review of cancer biology studies on KRAS and macropinocytosis.
- Analysis of recent research on exploiting macropinocytosis for drug delivery.
- Discussion of therapeutic opportunities and challenges.
Main Results:
- KRAS mutations are linked to increased macropinocytosis, crucial for nutrient uptake in tumors.
- Drug delivery systems can be internalized by KRAS-mutant cells via macropinocytosis.
- Exploiting macropinocytosis offers a novel route for targeted intracellular drug delivery.
Conclusions:
- Macropinocytosis represents a promising, albeit challenging, strategy for targeting KRAS-mutant cancers.
- Further research is needed to overcome potential pitfalls in this drug delivery expedition.
