Hippo pathway mediates resistance to cytotoxic drugs
Open accessAbstract
Significance: Cytotoxic therapy is still the backbone of effective chemotherapy, although most current pharmaceutical interest is in targeted therapy. Our findings concern a general adaptive response of cells that causes resistance to gemcitabine and 15 other FDA-approved cytotoxic drugs when cells are grown at high density. Although on the surface cell confluence seems like it could be an irrelevant property of cells in culture, our work shows that it is very relevant to tumors in mice and retrospectively to the success of chemotherapy in humans. On a fundamental cell biological level, these studies identify a previously unappreciated function of the enigmatic Hippo pathway, which controls this response. “Switching-off” this pathway could present an opportunity to overcome drug resistance in pancreatic cancer.
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- Authors
- Gujral, T. S., & Kirschner, M. W.
- Affiliations
- Harvard University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-04-17
- Volume
- 114
- Issue
- 18
- Pages
- E3729-E3738
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5422801
- OpenAlex
- W2605515821
- Cited by
- 91
- References
- 70
- Citations by year
- 2026: 11 · 2025: 7 · 2024: 11 · 2023: 11 · 2022: 11 · 2021: 12 · 2020: 12 · 2019: 11 · 2018: 4
- FWCI
- 3.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (R01 HD073104, R01 GM103785)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- Hippo signaling pathway, YAP, gemcitabine, chemoresistance, cell density, multidrug transporter, intracellular drug accumulation, tumor spheroids, patient-derived xenografts, cancer cell lines, drug repurposing
- MeSH terms
- Hippo Signaling Pathway, YAP-Signaling Proteins, Gemcitabine, Animals, Cell Line, Cytotoxins, Deoxycytidine, Humans, Neoplasms, Phosphoproteins, Transcription Factors, Signal Transduction, Protein Serine-Threonine Kinases, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Adaptor Proteins, Signal Transducing, Mice
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