Dual blockade of macropinocytosis and asparagine bioavailability shows synergistic anti-tumor effects on KRAS-mutant colorectal cancer
Open accessAbstract
Mutations of KRAS gene are found in various types of cancer, including colorectal cancer (CRC). Despite intense efforts, no pharmacological approaches are expected to be effective against KRAS-mutant cancers. Macropinocytosis is an evolutionarily conserved actin-dependent endocytic process that internalizes extracellular fluids into large vesicles called macropinosomes. Recent studies have revealed macropinocytosis's important role in metabolic adaptation to nutrient stress in cancer cells harboring KRAS mutations. Here we showed that KRAS-mutant CRC cells enhanced macropinocytosis for tumor growth under nutrient-depleted conditions. We also demonstrated that activation of Rac1 and phosphoinositide 3-kinase were involved in macropinocytosis of KRAS-mutant CRC cells. Furthermore, we found that macropinocytosis was closely correlated with asparagine metabolism. In KRAS-mutant CRC cells engineered with knockdown of asparagine synthetase, macropinocytosis was accelerated under glutamine-depleted condition, and albumin addition could restore the glutamine depletion-induced growth suppression by recovering the intracellular asparagine level. Finally, we discovered that the combination of macropinocytosis inhibition and asparagine depletion dramatically suppressed the tumor growth of KRAS-mutant CRC cells in vivo. These results indicate that dual blockade of macropinocytosis and asparagine bioavailability could be a novel therapeutic strategy for KRAS-mutant cancers.
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In RAS-mutant colorectal cancer, macropinocytosis is upregulated, and these cancer cells exhibit sensitivity to MP inhibitors.
“In RAS-mutant colorectal cancer, MP is indeed upregulated, and these cancer cells exhibit sensitivity to MP inhibitors [28,30].”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [30]
RAS mutations and the PI3K pathway contribute to macropinocytosis activation.
“RAS mutations and the PI3K pathway contribute to MP activation.”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [30]
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Wang, C., Wang, X., Jiang, Z., Zhao, J., Wang, X., Liu, Y., Yuan, J., & Jiao, Y. (2026) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2026.189655
Peng, X., Liu, S., & Tao, Y. (2026) · Experimental Hematology and Oncology · doi:10.1186/s40164-026-00812-1
- Authors
- Hanada, K., Kawada, K., Nishikawa, G., Toda, K., Maekawa, H., Nishikawa, Y., Masui, H., Hirata, W., Okamoto, M., Kiyasu, Y., Honma, S., Ogawa, R., Mizuno, R., Itatani, Y., Miyoshi, H., Sasazuki, T., Shirasawa, S., Taketo, M. M., Obama, K., & Sakai, Y.
- Affiliations
- Kyoto University (JP)
- Otsu Municipal Hospital (JP)
- Kobe City Medical Center West Hospital (JP)
- Uji-Tokushukai Medical Center (JP)
- Kyoto University Hospital (JP)
- Kyushu University (JP)
- Fukuoka University (JP)
- Osaka Red Cross Hospital (JP)
- Corresponding author
- Kawada, Kenji
- ORCID
- Venue
- Cancer Letters
- Publisher
- Elsevier BV
- Published
- 2021-12
- Volume
- 522
- Pages
- 129-141
- ISSN
- 0304-3835 (ISSN-L)
- OpenAlex
- W3199187959
- Cited by
- 27
- References
- 60
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 4 · 2023: 3 · 2022: 7
- FWCI
- 1.83
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Cancer Letters (publishedVersion)
- PubMed (publishedVersion)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- macropinocytosis, asparagine metabolism, KRAS-mutant colorectal cancer, asparagine synthetase, glutamine deprivation, albumin, Rac1, phosphatidylinositol 3-kinase, nutritional stress, tumor growth inhibition, combination therapy
- MeSH terms
- Asparagine, Aspartate-Ammonia Ligase, Humans, Mutation, Pinocytosis, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Phosphatidylinositol 3-Kinases, rac1 GTP-Binding Protein, Cell Line, Tumor, Cell Proliferation, Gene Knockdown Techniques
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