Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy
Open accessAbstract
Single-agent immunotherapy has achieved limited clinical benefit to date in patients with pancreatic ductal adenocarcinoma (PDAC). This may be a result of the presence of a uniquely immunosuppressive tumor microenvironment (TME). Critical obstacles to immunotherapy in PDAC tumors include a high number of tumor-associated immunosuppressive cells and a uniquely desmoplastic stroma that functions as a barrier to T cell infiltration. We identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as an important regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlated with high levels of fibrosis and poor CD8(+) cytotoxic T cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 substantially limited tumor progression, resulting in a doubling of survival in the p48-Cre;LSL-Kras(G12D);Trp53(flox/+) (KPC) mouse model of human PDAC. This delay in tumor progression was associated with markedly reduced tumor fibrosis and decreased numbers of tumor-infiltrating immunosuppressive cells. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.
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Targeting FAK in cancer cells concomitantly reduces stromal fibroblast activation and development of an immunosuppressive environment.
“and targeting focal adhesion kinase (FAK) in cancer cells concomitantly reduces stromal fibroblast activation and the development of an immunosuppressive environment123.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [123]
Randomized clinical trials combining PEG-hyaluronidase with standard-of-care chemotherapy for advanced PDAC did not increase overall survival, regardless of chemotherapy backbone or selection of patients with high hyaluronic acid by immunostaining.
“randomized clinical trials combining a pegylated hyaluronic acid degrading enzyme, PEG-hyaluronidase, with standard-of-care chemotherapy for advanced PDAC did not show an increase in overall survival regardless of chemotherapy backbone or selection of patients with high levels of hyaluronic acid by immunostaining172,173”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [173]
FAK inhibition may enhance KRAS (G12C) inhibition and immunotherapy.
“Thus, FAK inhibition may enhance KRAS (G12C) inhibition and immunotherapy [125, 126].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [125]
FAK-related fibrosis can form a barrier in tumors that limits the CD8+ T cells infiltration in tumors, and FAK inhibition can ultimately promote the antitumor effects by decreasing the number of tumor-resident Tregs.
“FAK-related fibrosis can form a barrier in tumors that limits the CD8+ T cells infiltration in tumors, and FAK inhibition can ultimately promote the antitumor effects by decreasing the number of tumor-resident Tregs.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [125]
FAK signaling regulates fibrogenesis within tumors.
“FAK signaling has been reported to regulate fibrogenesis within tumors,[ 17, 48 ] and excessive fibrosis is correlated with drug resistance, because it can create a barrier that prevents interactions between cancer cells and therapeutic agents.[ 49 ]”
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 [17]
Combined benefits from a PD1 antibody in combination with FAK inhibition against KRAS mutant cancer have been reported.
“There is reported evidence showing combined benefits from a PD1 antibody in combination with FAK inhibition against KRAS mutant cancer.[ 17 ]”
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 [17]
Developing pancreatic tumor-on-a-chip systems for in vitro experiments is essential for enhancing pancreatic drug screening efficiency before animal model testing and clinical trials.
“Since pancreatic cancers are invasive solid tumors with hypovascular structures and extensive fibrosis214, developing pancreatic tumor-on-a-chip systems for in vitro experiments is essential for enhancing pancreatic drug screening efficiency before animal model testing and clinical trials.”
From Tumor-on-a-chip: from bioinspired design to biomedical application (2021) · cites this paper as [214]
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- Authors
- Jiang, H., Hegde, S., Knolhoff, B. L., Zhu, Y., Herndon, J. M., Meyer, M. A., Nywening, T. M., Hawkins, W. G., Shapiro, I. M., Weaver, D. T., Pachter, J. A., Wang-Gillam, A., & DeNardo, D. G.
- Affiliations
- Washington University in St. Louis (US)
- Verastem (United States) (US)
- Corresponding author
- DeNardo, David G
- ORCID
- Venue
- Nature Medicine
- Published
- 2016-07-04
- Volume
- 22
- Issue
- 8
- Pages
- 851-860
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4935930
- OpenAlex
- W2469223980
- Cited by
- 1,060
- References
- 57
- Citations by year
- 2026: 108 · 2025: 82 · 2024: 126 · 2023: 114 · 2022: 99 · 2021: 135 · 2020: 129 · 2019: 94 · 2018: 90 · 2017: 68 · 2016: 13 · 2014: 1
- FWCI
- 47.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (KL2TR000450)
- National Cancer Institute (R21CA182701, P50CA196510, F99CA223043, R01CA177670, R01CA203890, T32CA009621, T32CA113275, P30CA091842)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Peptidase Inhibition and Analysis
- Keywords
- focal adhesion kinase, pancreatic ductal adenocarcinoma, immunotherapy resistance, tumor microenvironment, tumor fibrosis, desmoplasia, CD8+ T cell infiltration, VS-4718, FAK inhibition, T cell checkpoint blockade, KPC mouse model
- MeSH terms
- Gemcitabine, Aminopyridines, Animals, Antimetabolites, Antineoplastic, Deoxycytidine, Disease Models, Animal, Fibrosis, Humans, Immunohistochemistry, Immunotherapy, Pancreatic Neoplasms, Immunoblotting, Immunotherapy, Adoptive, CD8-Positive T-Lymphocytes, Disease Progression, Tumor Escape, Reverse Transcriptase Polymerase Chain Reaction, Carcinoma, Pancreatic Ductal, Cell Proliferation, Mice, Focal Adhesion Protein-Tyrosine Kinases, Tumor Microenvironment, Programmed Cell Death 1 Receptor
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