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

Abstract

Background Pancreatic ductal adenocarcinoma (PDAC) is a very lethal disease, with minimal therapeutic options. Aberrant tyrosine kinase activity influences tumor growth and is regulated by phosphorylation. We investigated phosphorylated kinases as target in PDAC. Methods Mass spectrometry-based phosphotyrosine proteomic analysis on PDAC cell lines was used to evaluate active kinases. Pathway analysis and inferred kinase activity analysis was performed to identify novel targets. Subsequently, we investigated targeting of focal adhesion kinase (FAK) in vitro with drug perturbations in combination with chemotherapeutics used against PDAC. Tyrosine phosphoproteomics upon treatment was performed to evaluate signaling. An orthotopic model of PDAC was used to evaluate the combination of defactinib with nab-paclitaxel. Results PDAC cell lines portrayed high activity of multiple receptor tyrosine kinases to various degree. The non-receptor kinase, FAK, was identified in all cell lines by our phosphotyrosine proteomic screen and pathway analysis. Targeting of this kinase with defactinib validated reduced phosphorylation profiles. Additionally, FAK inhibition had anti-proliferative and anti-migratory effects. Combination with (nab-)paclitaxel had a synergistic effect on cell proliferation in vitro and reduced tumor growth in vivo. Conclusions Our study shows high phosphorylation of several oncogenic receptor tyrosine kinases in PDAC cells and validated FAK inhibition as potential synergistic target with Nab-paclitaxel against this devastating disease.

Biological Hallmarks and New Therapeutic Approaches for the Treatment of PDAC

“…Targeting FAK kinase, in association with other therapeutic options in pancreatic tumors could be an attractive strategy. As reported [ 90 ], FAK inhibition synergizes with nab-paclitaxel in preclinical models of PDAC cells. Moreover [ 91 , 92 ], in preclinical PDAC models, the inhibition of FAK kinase sensitizes cancer cells to radiotherapy, enhancing CD8+ T-cell infiltration in the TME and a consequent reduction of granulocyte population.…”

Application of Mass Spectrometry in Pancreatic Cancer Translational Research

“…The phosphoproteome analysis by Le and his colleagues confirmed the role of focal adhesion kinase (FAK) as a new target for PDAC. FAK was the core participant of hyperphosphorylated tyrosine kinases in PDAC, while the combination of FAK inhibitors with paclitaxel showed a synergistic anti-tumor effect on PDAC cells in vitro and in vivo ( 107 ). Besides protein phosphorylation, abnormal ubiquitin also plays an essential role in cancer metastasis.…”

SF3B1 modulators affect key genes in metastasis and drug influx: a new approach to fight pancreatic cancer chemoresistance

“…Panc05.04 is a pancreatic adenocarcinoma epithelial cell line derived, in 1995, from a primary tumour resected from the head of the pancreas of a woman with PDAC (ATCC® catalogue number CRL-2557™). The PDAC-3 primary culture cells were obtained from patients undergoing pancreatoduodenectomy, as described previously [52] . PDAC-3, SUIT-2 and Hs766t cells were cultured in RPMI-1640 (Roswell Park Memorial Institute 1640) and DMEM (Dulbecco's Modified Eagle's Medium) medium, respectively, supplemented with 10% NBCS and 1% penicillin/streptomycin.…”