Macropinocytosis confers resistance to therapies targeting cancer anabolism
Open accessAbstract
Macropinocytic cancer cells scavenge amino acids from extracellular proteins. Here, we show that consuming necrotic cell debris via macropinocytosis (necrocytosis) offers additional anabolic benefits. A click chemistry-based flux assay reveals that necrocytosis provides not only amino acids, but sugars, fatty acids and nucleotides for biosynthesis, conferring resistance to therapies targeting anabolic pathways. Indeed, necrotic cell debris allow macropinocytic breast and prostate cancer cells to proliferate, despite fatty acid synthase inhibition. Standard therapies such as gemcitabine, 5-fluorouracil (5-FU), doxorubicin and gamma-irradiation directly or indirectly target nucleotide biosynthesis, creating stress that is relieved by scavenged nucleotides. Strikingly, necrotic debris also render macropinocytic, but not non-macropinocytic, pancreas and breast cancer cells resistant to these treatments. Selective, genetic inhibition of macropinocytosis confirms that necrocytosis both supports tumor growth and limits the effectiveness of 5-FU in vivo. Therefore, this study establishes necrocytosis as a mechanism for drug resistance.
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Macropinocytosis has been implicated in resistance to tyrosine kinase inhibitors and standard-of-care agents such as gemcitabine and 5-FU.
“Macropinocytosis has also been implicated in resistance to tyrosine kinase inhibitors and standard-of-care agents, such as gemcitabine and 5-fluorouracil (5-FU).34,35”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [35]
The Discussion reports that 5-FU and gemcitabine were ineffective when cells could perform necrocytosis, with resistance also observed in macropinocytic tumors in vivo. The cited passages do not establish resistance to tyrosine kinase inhibitors, so that part of the sentence is unsupported by this source. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPDAC cells utilize macropinocytosis to obtain amino acids through uptake and degradation of albumin and collagen.
“PDAC cells utilize macropinocytosis to obtain amino acids through the uptake and degradation of albumin and collagen230–232”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [232]
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Macropinocytosis at the crossroad between nutrient scavenging and metabolism in cancer
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Gold Nanoparticles Inhibit Macropinocytosis by Decreasing KRAS Activation
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- Authors
- Jayashankar, V., & Edinger, A. L.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Edinger, Aimee L.
- ORCID
- Edinger, Aimee L.
- Venue
- Nature Communications
- Published
- 2020-02-28
- Volume
- 11
- Issue
- 1
- Pages
- 1121-1121
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7048872
- OpenAlex
- W3009504922
- Cited by
- 200
- References
- 71
- Citations by year
- 2026: 21 · 2025: 46 · 2024: 40 · 2023: 28 · 2022: 27 · 2021: 29 · 2020: 9
- FWCI
- 7.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Johns Hopkins University
- Ionis Pharmaceuticals
- Cancer Research Coordinating Committee (CRR-17-426826)
- National Institutes of Health (W81XWH-15-1-0010, W81XWH)
- University of California, Irvine (P30CA‐062203, W81XWH-15-1-0010)
- National Cancer Institute (R01CA247556, P30CA062203)
- Chao Family Comprehensive Cancer Center (P30 CA062203)
- UCI Beall Applied Innovation
- Congressionally Directed Medical Research Programs (W81XWH-15-1-0010)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- macropinocytosis, drug resistance, nucleotide synthesis, fatty acid synthase inhibition, 5-fluorouracil, gemcitabine, doxorubicin, gamma irradiation, breast cancer, prostate cancer, pancreatic cancer, tumor growth
- MeSH terms
- Nutrients, Animals, Antimetabolites, Antineoplastic, Breast Neoplasms, Female, Fluorouracil, Humans, Microfilament Proteins, Mutation, Pinocytosis, Drug Resistance, Neoplasm, Cell Line, Tumor, Cell Proliferation, Mice, Fatty Acid Synthases, Metabolic Flux Analysis
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Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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