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

T Y S Le Large,N Funel,J C Knol,L Morelli,B El Hassouni,T Lagerweij,S R Piersma,C R Jimenez,G Kazemier,E Giovannetti,T V Pham,A A Henneman,H W M Van Laarhoven,G Mantini,M F Bijlsma,R De Haas,B Kok

doi:10.1186/s13046-021-01892-z

Abstract

BackgroundPancreatic 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.MethodsMass 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.ResultsPDAC 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.ConclusionsOur 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.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is a very lethal disease, with minimal therapeutic options
Phosphoproteomic analysis reveal abundant phosphorylated kinases in PDAC As the cellular signaling that drives cancer depends largely on the aberrant phosphorylation of kinases, the phosphoproteome of a panel of cell lines of PDAC incorporating the full heterogeneity of the disease was analyzed after enrichment for phosphotyrosine peptides
The data include a wide range of the human kinome [27], including 60% of the known human receptor tyrosine kinases (RTKs) and 68% of the known non-receptor tyrosine kinases

Summary

Introduction

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. Pancreatic ductal adenocarcinoma (PDAC) is an unsolved major health problem, with only 9% of patients alive 5 years after diagnosis [1]. Surgery offers the only curative treatment, but most patients present with advanced disease, at which point palliative chemotherapy is the only option to slow disease progression. Second- and third-line treatment options are not standardized and new therapies are warranted. Targeting aberrantly activated tyrosine kinases by tyrosine kinase inhibitors (TKIs) has proven successful in several other solid tumors, for example targeting the mutated epithelial growth factor receptor (EGFR) in non-small cell lung carcinoma [4], or mutated Serine/threonine-protein kinase B-raf in melanoma [5]. Similar successes have not been achieved to date in PDAC

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