FAK activity in cancer‐associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer

Abstract

Cancer‐associated fibroblasts (CAFs) are considered the most abundant type of stromal cells in pancreatic ductal adenocarcinoma (PDAC), playing a critical role in tumour progression and chemoresistance; however, a druggable target on CAFs has not yet been identified. Here we report that focal adhesion kinase (FAK) activity (evaluated based on 397 tyrosine phosphorylation level) in CAFs is highly increased compared to its activity in fibroblasts from healthy pancreas. Fibroblastic FAK activity is an independent prognostic marker for disease‐free and overall survival of PDAC patients (cohort of 120 PDAC samples). Genetic inactivation of FAK within fibroblasts (FAK kinase‐dead, KD) reduces fibrosis and immunosuppressive cell number within primary tumours and dramatically decreases tumour spread. FAK pharmacologic or genetic inactivation reduces fibroblast migration/invasion, decreases extracellular matrix (ECM) expression and deposition by CAFs, modifies ECM track generation and negatively impacts M2 macrophage polarization and migration. Thus, FAK activity within CAFs appears as an independent PDAC prognostic marker and a druggable driver of tumour cell invasion.

Focal adhesion kinase inhibition synergizes with nab-paclitaxel to target pancreatic ductal adenocarcinoma

“…Upon inhibition of FAK, these tumors were more sensitive to immune targeting therapy [51], prompting interest in FAK inhibition in combination with immunotherapy. Moreover, FAK inhibition affects cancer-associated fibroblast in the tumor microenvironment [52], further enhancing the functionality of targeting this kinase in PDAC patients.…”

Stromal Protein-Mediated Immune Regulation in Digestive Cancers

“…Indeed, Zaghdoudi and colleagues showed in a pre-clinical model of pancreatic cancer that FAK inhibition within fibroblasts resulted in increased sensitivity to chemotherapy and immune checkpoint inhibitor blockade. Moreover, they observed a decrease in the occurrence of metastases [ 231 ]. Currently, targeting FAK activity is evaluated in several phase I-II clinical trials as monotreatment, as well as in combination with programmed cell death protein 1 (NCT02758587) or mitogen-activated protein kinase kinase (MEK) inhibitors (NCT02428270).…”

The Adhesome Network: Key Components Shaping the Tumour Stroma

“…In other studies, chemical inhibition of FAK resulted in tumour stasis by reducing stroma proliferation and limiting the presence of FAP + and aSMA + CAFs [ 21 , 22 ]. Moreover, FAK activity in CAFs was recently found to drive tumour metastasis and augment an immunosuppressive TME [ 25 , 26 ]. Taken together, these studies provide evidence for a role of FAK in mediating the tumour-promoting actions of CAFs in vivo.…”