Hui-Deng Long, Hao Wang, Wei Xiang, Tian-Yin Ma, Ting-Ting Du, Su-Feng Zhang, Fu-Xing Liu, Zi-Yu Chen, Cui-Ni Lu, Xin-Yun Liu, Xiao-Feng Wang, Tian Gong, Ning Han, Yue-Feng Cai, Chun Yang, Dong-Feng Chen, En-Yu Liu, Da Fu, Hong Yu, Wen-Guang Wu, Yu-Shui Ma
Pancreatic cancer (PC) is a highly lethal malignancy characterized by aggressive progression and limited treatment options. Current standard-of-care treatments only confer marginal survival benefits, highlighting an urgent unmet clinical need to identify novel actionable targets and mechanism-driven therapeutic regimens. Focal adhesion kinase (FAK, encoded by PTK2) is frequently dysregulated across a broad spectrum of cancers and tightly associated with malignant tumor phenotypes, yet its precise clinical relevance and druggable potential in PC remain incompletely elucidated. This study systematically evaluated the diagnostic and prognostic value of PTK2/FAK in PC, and dissected the anti-tumor efficacy and underlying molecular mechanism of the selective FAK inhibitor Defactinib. We confirmed that PTK2 was significantly overexpressed in PC tissues, serving as a high-accuracy diagnostic biomarker with an AUC of 0.959 and an independent risk factor for unfavorable prognosis. PTK2-high tumors exhibited marked enrichment of the PI3K/AKT oncogenic signaling pathway, and MYC was validated to directly transcriptionally upregulate PTK2, where patients with concurrent MYC-high and PTK2-high tumors showed the worst clinical outcomes. Using in vitro functional assays and two distinct genetically engineered mouse models, we demonstrated that Defactinib potently suppressed tumor proliferation and induced caspase-3-dependent apoptosis via blockade of the PI3K/AKT cascade. Notably, Defactinib also triggered ULK1-mediated compensatory protective autophagy, and co-administration with the autophagy inhibitor chloroquine effectively abrogated this process to substantially amplify the anti-tumor effect. Our findings validate PTK2 as a clinically meaningful prognostic biomarker and promising therapeutic target, providing robust new preclinical evidence to support the clinical translation of PTK2-targeted combination therapies for PC.