FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy
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Abstract
Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance.
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Activation of FAK signaling has been proposed as a mechanism underlying resistance to targeted therapies.
“activation of FAK signaling has been proposed as a mechanism underlying resistance to target therapies, specifically because of its impacts on multiple aspects of the tumor microenvironment.[ 15, 16 ]”
From Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling (2021) · cites this paper as [15]
FAK activation is implicated in the development of resistance against various chemotherapy agents through its regulation of the tumor microenvironment.
“Interestingly, multiple previous studies have implicated FAK activation in the development of resistance against various chemotherapy agents through its regulation of the tumor microenvironment.[ 11, 15, 44 ]”
From Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling (2021) · cites this paper as [15]
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Cites
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Self-citationMachine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation
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Self-citationFAK in cancer: mechanistic findings and clinical applications
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FAK Structure and Regulation by Membrane Interactions and Force in Focal Adhesions
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- Authors
- Diaz Osterman, C. J., Ozmadenci, D., Kleinschmidt, E. G., Taylor, K. N., Barrie, A. M., Jiang, S., Bean, L. M., Sulzmaier, F. J., Jean, C., Tancioni, I., Anderson, K., Uryu, S., Cordasco, E. A., Li, J., Chen, X. L., Fu, G., Ojalill, M., Rappu, P., Heino, J., Mark, A. M., Xu, G., Fisch, K. M., Kolev, V. N., Weaver, D. T., Pachter, J. A., Győrffy, B., McHale, M. T., Connolly, D. C., Molinolo, A., Stupack, D. G., & Schlaepfer, D. D.
- Affiliations
- Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States
- University of California San Diego (US)
- Xiamen University (CN)
- University of Turku (FI)
- Verastem (United States) (US)
- Semmelweis University (HU)
- Fox Chase Cancer Center (US)
- Corresponding author
- Stupack, Dwayne G
- Schlaepfer, David D
- ORCID
- Ozmadenci, Duygu
- Taylor, Kristin N
- Jiang, Shulin
- Bean, Lisa M
- Sulzmaier, Florian J
- Jean, Christine
- Tancioni, Isabelle
- Anderson, Kristen
- Uryu, Sean
- Cordasco, Edward A
- Li, Jian
- Chen, Xiao Lei
- Fu, Guo
- Ojalill, Marjaana
- Rappu, Pekka
- Heino, Jyrki
- Fisch, Kathleen M
- Kolev, Vihren N
- Weaver, David T
- Pachter, Jonathan A
- Győrffy, Balázs
- McHale, Michael T
- Connolly, Denise C
- Molinolo, Alfredo
- Stupack, Dwayne G
- Schlaepfer, David D
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2019-09-03
- Volume
- 8
- Pages
- e47327
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC6721800
- OpenAlex
- W2971694758
- Cited by
- 145
- References
- 3
- Citations by year
- 2026: 16 · 2025: 18 · 2024: 24 · 2023: 21 · 2022: 24 · 2021: 25 · 2020: 13 · 2019: 1 · 2018: 2
- FWCI
- 15.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- HAL (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Semmelweis University Repository (Semmelweis University) (submittedVersion)
- Funders
- National Institutes of Health (RO1 CA180769, RO1 CA102310, RO1 CA107263, T32 CA121938, P30 CA023100, UL1 TR001442, T36 GM095349, P30 CA006927, RO1 CA195723)
- United States Department of Defense (W81XWH-16-1-0142, W81XWH-19-1-0134)
- Medical Research Council of Hungary (NVKP_16-1-2016-0037, 2018-1.3.1-VKE-2018-00032, KH-129581)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- focal adhesion kinase, platinum resistance, high-grade serous ovarian cancer, chemoresistance, KRAS, c-Myc, FAK tyrosine phosphorylation, tumor spheres, aldehyde dehydrogenase, Wnt/β-catenin signaling, FAK inhibitors, cisplatin, copy number alterations, cancer stemness, DNA repair genes, pluripotency genes, apoptosis
- MeSH terms
- Animals, Antineoplastic Agents, Cisplatin, Disease Models, Animal, Female, Humans, Ovarian Neoplasms, Platinum, Stem Cells, Signal Transduction, Proto-Oncogene Proteins c-myc, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm, Mice, Focal Adhesion Kinase 1
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