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Updated: Mar 18, 2026
Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma
Published on: November 19, 2019
Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy
Hong Jiang1,2, Samarth Hegde1,2, Brett L Knolhoff1,2
1Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Abstract:
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.
Insights
Targeting focal adhesion kinase (FAK) in pancreatic ductal adenocarcinoma (PDAC) reduces tumor fibrosis and immunosuppressive cells. FAK inhibition enhances immunotherapy effectiveness in PDAC models.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits limited response to single-agent immunotherapy.
- The immunosuppressive tumor microenvironment (TME) in PDAC, characterized by stromal desmoplasia and immunosuppressive cells, impedes T cell infiltration and anti-tumor immunity.
Purpose of the Study:
- To investigate the role of focal adhesion kinase (FAK) in regulating the PDAC TME.
- To evaluate the therapeutic potential of FAK inhibition, alone and in combination with immunotherapy, in PDAC models.
Main Methods:
- Analysis of FAK activity in human PDAC tissues.
- Assessment of FAK activity correlation with fibrosis and CD8(+) T cell infiltration.
- Evaluation of the selective FAK inhibitor VS-4718 in a KPC mouse model of PDAC.
- Combination therapy studies involving FAK inhibition, T cell immunotherapy, and PD-1 antagonists.
Main Results:
- Elevated FAK activity was observed in human PDAC tissues, correlating with increased fibrosis and reduced CD8(+) T cell infiltration.
- Single-agent FAK inhibition with VS-4718 significantly delayed tumor progression and doubled survival in KPC mice.
- FAK inhibition led to reduced tumor fibrosis and decreased numbers of immunosuppressive cells within the TME.
- FAK inhibition sensitized the PDAC TME to T cell immunotherapy and PD-1 antagonists, overcoming prior unresponsiveness.
Conclusions:
- Hyperactivated FAK in PDAC cells is a key regulator of the fibrotic and immunosuppressive TME.
- Targeting FAK represents a promising strategy to overcome TME-mediated resistance to immunotherapy in PDAC.
- FAK inhibition can enhance immune surveillance and render PDAC tumors more responsive to existing immunotherapeutic agents.
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