Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells

Osipov, Arsen; Blair, Alex B.; Liberto, Juliane; Wang, Jianxin; Li, Keyu; Herbst, Brian T.; Xu, Yao−Zhong; Li, Shiqi; Niu, Nan; Rashid, Rufiaat; Ding, Ding; Liu, Yanan; Wang, Zaiqi; Wolfgang, Christopher L.; Burkhart, Richard A.; Laheru, Daniel A.; Zheng, Lei

doi:10.20892/j.issn.2095-3941.2020.0273

Cited by 22 publications

(14 citation statements)

References 38 publications

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Section: Other Strategies To Target Fak In Pancreatic and Other Cancersmentioning

confidence: 99%

“…In PDAC, IN10018, a small molecule inhibitor of FAK, was shown to enhance the anti-tumour efficacy of radiotherapy, which resulted in reduced tumour growth and increased survival [ 49 ]. Further investigation revealed that this effect was due to an increase in anti-tumorigenic CD8+ T cells and an inhibition of infiltrating pro-tumourigenic granulocytes [ 49 ]. Similarly, a recent study using antibody-driven expression of the T cell stimulatory ligands CD80, 4-1bb and OX40 sensitised SCC and PC cells to FAK inhibition in combination with gemcitabine [ 86 ].…”

Section: Other Strategies To Target Fak In Pancreatic and Other Cancersmentioning

confidence: 99%

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Focal adhesion kinase priming in pancreatic cancer, altering biomechanics to improve chemotherapy

Murphy

Zhu

Trpceski

et al. 2022

Biochemical Society Transactions

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The dense desmoplastic and fibrotic stroma is a characteristic feature of pancreatic ductal adenocarcinoma (PDAC), regulating disease progression, metastasis and response to treatment. Reciprocal interactions between the tumour and stroma are mediated by bidirectional integrin-mediated signalling, in particular by Focal Adhesion Kinase (FAK). FAK is often hyperactivated and overexpressed in aggressive cancers, promoting stromal remodelling and inducing tissue stiffness which can accelerate cancer cell proliferation, survival and chemoresistance. Therapeutic targeting of the PDAC stroma is an evolving area of interest for pre-clinical and clinical research, where a subtle reshaping of the stromal architecture prior to chemotherapy may prove promising in the clinical management of disease and overall patient survival. Here, we describe how transient stromal manipulation (or ‘priming’) via short-term FAK inhibition, rather than chronic treatment, can render PDAC cells exquisitely vulnerable to subsequent standard-of-care chemotherapy. We assess how our priming publication fits with the recent literature and describe in this perspective how this could impact future cancer treatment. This highlights the significance of treatment timing and warrants further consideration of anti-fibrotic therapies in the clinical management of PDAC and other fibrotic diseases.

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Section: Other Strategies To Target Fak In Pancreatic and Other Cancersmentioning

confidence: 99%

Section: Other Strategies To Target Fak In Pancreatic and Other Cancersmentioning

confidence: 99%

Focal adhesion kinase priming in pancreatic cancer, altering biomechanics to improve chemotherapy

Murphy

Zhu

Trpceski

et al. 2022

Biochemical Society Transactions

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“…Pre-clinically, FAK inhibition decreased tumor cell proliferation, reduced tumor-associated macrophages and CAFs, increased CD8+ T cell infiltration, and sensitized tumors to RT. [157,158] A phase I trial of defactinib, an oral FAK1 TKI, in combination pembrolizumab and gemcitabine (NCT02546531) showed modest but encouraging efficacy signals in both maintenance and treatment refractory mPDAC settings [159]. Correlative studies with paired biopsies in PDAC patients show increased proliferating CD8+ T cells, while Tregs, macrophages, and stromal density decreased with treatment [159].…”

Section: Il-1β Antagonismmentioning

confidence: 99%

Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance

Heumann

Azad

2021

Cancer Metastasis Rev

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To date, the use of immune checkpoint inhibitors has proven largely ineffective in patients with advanced pancreatic ductal adenocarcinoma. A combination of low tumor antigenicity, deficits in immune activation along with an exclusive and suppressive tumor microenvironment result in resistance to host defensives. However, a deepening understanding of these immune escape and suppressive mechanisms has led to the discovery of novel molecular targets and treatment strategies that may hold the key to a long-awaited therapeutic breakthrough. In this review, we describe the tumor-intrinsic and microenvironmental barriers to modern immunotherapy, examine novel immune-based and targeted modalities, summarize relevant pre-clinical findings and human experience, and, finally, discuss novel synergistic approaches to overcome immune-resistance in pancreatic cancer. Beyond checkpoint inhibition, immune agonists and anti-tumor vaccines represent promising strategies to stimulate host response via activation and expansion of anti-tumor immune effectors. Off-the-shelf natural killer cell therapies may offer an effective method for bypassing downregulated tumor antigen presentation. In parallel with this, sophisticated targeting of crosstalk between tumor and tumor-associated immune cells may lead to enhanced immune infiltration and survival of antitumor lymphocytes. A future multimodal treatment strategy involving immune priming/activation, tumor microenvironment reprogramming, and immune checkpoint blockade may help transform pancreatic cancer into an immunogenic tumor.

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“…Six patients (29%) achieved a complete response (CR), suggesting that IN10018 exhibits good antitumor activity. IN10018 will soon enter into phase I clinical trials, including IN10018 in combination with cobimetinib for metastatic melanoma, with conventional chemotherapy for advanced plasma cancer, and with Docetaxel for gastric cancer [ 71 , 72 ].…”

Section: The Development Of Fak Inhibitorsmentioning

confidence: 99%

Focal adhesion kinase inhibitors, a heavy punch to cancer

et al. 2021

Discov Onc

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Kinases are the ideal druggable targets for diseases and especially were highlighted on cancer therapy. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase and its aberrant signaling extensively implicates in the progression of most cancer types, involving in cancer cell growth, adhesion, migration, and tumor microenvironment (TME) remodeling. FAK is commonly overexpressed and activated in a variety of cancers and plays as a targetable kinase in cancer therapy. FAK inhibitors already exhibited promising performance in preclinical and early-stage clinical trials. Moreover, substantial evidence has implied that targeting FAK is more effective in combination strategy, thereby reversing the failure of chemotherapies or targeted therapies in solid tumors. In the current review, we summarized the drug development progress, chemotherapy strategy, and perspective view for FAK inhibitors.

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Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells

Cited by 22 publications

References 38 publications

Focal adhesion kinase priming in pancreatic cancer, altering biomechanics to improve chemotherapy

Focal adhesion kinase priming in pancreatic cancer, altering biomechanics to improve chemotherapy

Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance

Focal adhesion kinase inhibitors, a heavy punch to cancer

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