TY - JOUR
T1 - Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells
AU - Osipov, Arsen
AU - Blair, Alex B.
AU - Liberto, Juliane
AU - Wang, Jianxin
AU - Li, Keyu
AU - Herbst, Brian
AU - Xu, Yao
AU - Li, Shiqi
AU - Niu, Nan
AU - Rashid, Rufiaat
AU - Ding, Ding
AU - Liu, Yanan
AU - Wang, Zaiqi
AU - Wolfgang, Christopher L.
AU - Burkhart, Richard A.
AU - Laheru, Daniel
AU - Zheng, Lei
N1 - Funding Information:
Lei Zheng receives grant support from Bristol-Meyer Squibb, Merck, iTeos, Amgen, NovaRock, Inxmed, and Halozyme. Lei Zheng is a paid consultant/Advisory Board Member at Biosion, Alphamab, NovaRock, Akrevia, Datarevive, and Mingruzhiyao. Lei Zheng holds shares at Alphamab and Mingruzhiyao. Yanan Liu and Zaiqi Wang are employees of InxMed. Zaiqi Wang is a shareholder of InxMed. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2021 Cancer Biology & Medicine.
PY - 2021/2
Y1 - 2021/2
N2 - 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.
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.
KW - Focal adhesion protein-tyrosine kinases
KW - Immunomodulation
KW - Pancreatic neoplasms
KW - Radiotherapy
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U2 - 10.20892/j.issn.2095-3941.2020.0273
DO - 10.20892/j.issn.2095-3941.2020.0273
M3 - Article
C2 - 33628595
AN - SCOPUS:85101103584
SN - 2095-3941
VL - 18
SP - 206
EP - 214
JO - Cancer Biology and Medicine
JF - Cancer Biology and Medicine
IS - 1
ER -