RT Journal Article
SR Electronic
T1 Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells
JF Cancer Biology and Medicine
JO Cancer Biol Med
FD China Anti-Cancer Association
SP 206
OP 214
DO 10.20892/j.issn.2095-3941.2020.0273
VO 18
IS 1
A1 Arsen Osipov
A1 Alex B. Blair
A1 Juliane Liberto
A1 Jianxin Wang
A1 Keyu Li
A1 Brian Herbst
A1 Yao Xu
A1 Shiqi Li
A1 Nan Niu
A1 Rufiaat Rashid
A1 Ding Ding
A1 Yanan Liu
A1 Zaiqi Wang
A1 Christopher  L. Wolfgang
A1 Richard A. Burkhart
A1 Daniel Laheru
A1 Lei Zheng
YR 2021
UL http://www.cancerbiomed.org/content/18/1/206.abstract
AB Objective: Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy, due in large part to its resistance to conventional therapies, including radiotherapy (RT). Despite RT exerting a modest antitumor response, it has also been shown to promote an immunosuppressive tumor microenvironment. Previous studies demonstrated that focal adhesion kinase inhibitors (FAKi) in clinical development inhibit the infiltration of suppressive myeloid cells and T regulatory (T regs) cells, and subsequently enhance effector T cell infiltration. FAK inhibitors in clinical development have not been investigated in combination with RT in preclinical murine models or clinical studies. Thus, we investigated the impact of FAK inhibition on RT, its potential as an RT sensitizer and immunomodulator in a murine model of PDAC.Methods: We used a syngeneic orthotopic murine model to study the effect of FAKi on hypofractionated RT.Results: In this study we showed that IN10018, a small molecular FAKi, enhanced antitumor response to RT. Antitumor activity of the combination of FAKi and RT is T cell dependent. FAKi in combination with RT enhanced CD8+ T cell infiltration significantly in comparison to the radiation or FAKi treatment alone (P < 0.05). FAKi in combination with radiation inhibited the infiltration of granulocytes but enhanced the infiltration of macrophages and T regs in comparison with the radiation or FAKi treatment alone (P < 0.01).Conclusions: These results support the clinical development of FAKi as a radiosensitizer for PDAC and combining FAKi with RT to prime the tumor microenvironment of PDAC for immunotherapy.