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Tyrosine phosphoproteomics of patient-derived xenografts reveals ephrin type-B receptor 4 tyrosine kinase as novel therapeutic target in pancreatic cancer

ABSTRACT: Pancreatic ductal adenocarcinoma is a recalcitrant tumor with minimal response to conventional chemotherapeutic approaches. Oncogenic signaling by activated tyrosine kinases has been implicated in cancers resulting in activation of diverse effector signaling pathways. Thus, discovery of aberrantly activated tyrosine kinases is of great interest in developing novel therapeutic strategies in treatment and management of pancreatic cancer. Patient-derived tumor xenografts (PDXs) in immunodeficient mice serve as potentially valuable preclinical model as it maintain the histological and molecular heterogeneity of the progenitor human tumor. Here, we employed high resolution mass spectrometry combined with immuno-affinity purification using anti-phosphotyrosine antibodies to profile tyrosine phosphoproteome across 13 pancreatic ductal adenocarcinoma PDX models. This analysis resulted in identification of 1,219 tyrosine phosphorylated sites mapping on 724 proteins. The mass spectrometric analysis revealed widespread and heterogeneous activation of both receptor and non-receptor tyrosine kinases. Studies carried out in mice confirmed ephrin type-B receptor 4 (EphB4) as a potential therapeutic target based on the efficacy of human serum albumin-conjugated soluble EphB4 in mice bearing orthotopic xenografts. In summary, we present the comprehensive landscape of tyrosine phosphoproteome with EphB4 as a promising therapeutic target in pancreatic ductal adenocarcinoma.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Pancreas

DISEASE(S): Pancreatic Ductal Carcinoma

SUBMITTER: Akhilesh Pandey

LAB HEAD: Akhilesh Pandey

PROVIDER: PXD021729 | Pride | 2021-05-24

REPOSITORIES: Pride

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Project description:Pancreatic ductal adenocarcinoma is one of the most lethal cancers, with a 5 year-survival rate below 5%. Lack of curative treatment and failure of targeted therapies urge the need to identify novel efficient therapeutic strategy. Achievement of this goal will be obtained through the identification of diagnosis and prognosis biomarkers, identification of novel therapeutic targets and the knowledge of resistance mechanisms induced by these targeted therapies. PI3K/Akt/mTOR signalling, one of the most altered in cancers, is overactivated in pancreatic cancer and correlated with poor prognosis. In the Vertebrates, the family of class I phosphoinoitide-3-kinase (PI3K) includes four isoforms: p110α, p110β, p110δ and p110γ. Although they all perform the same biochemical reaction (phosphorylation of PIP2 in PIP3, a membrane lipid messenger), each isoform were demonstrated to have specific physiological roles. Global PI3K inhibitors are currently being tested in phase I/II clinical trials in advanced solid cancers, but show at maximal doses tolerated a limited therapeutic benefit. Isoform-selective PI3K inhibitors are currently the most promising agents because, at low doses, they are more efficient to inhibit one PI3K isoform, and thus, less toxic than pan-PI3K inhibitors. The objectives of this thesis are to determine isoform-specific PI3K roles and the therapeutic interest to target one or more isoforms in pancreatitis and PDAC, by the identification of isoform-specific pathways and the study of adaptive responses induced by targeting of one or all isoforms of PI3K. In a first part, my work has highlighted, validated and completed results obtained in the team, to demonstrate the significance of PI3K/Akt signalling in two physiological processes: chronic pancreatitis and initiation of pancreatic carcinogenesis. Precisely, the overactivation of PI3K/Akt pathway measured on human and murine chronic pancreatitis samples is correlated with a specific p110α activation gene expression signature. Moreover, genetic and pharmacologic inactivation of p110α during pancreatic chronic inflammation or cancerogenesis (by oncogenic Kras) prevents the formation of acino-ductal metaplasia, structures at the origin of pancreatic carcinogenesis initiation. Development of in vitro acino-ductal transdifferentiation protocol allowed me to demonstrate that only p110α is necessary at this initial step of pancreatic carcinogenesis by the regulation of Rho small GTPases, further regulating actin remodelling. In the second part, by a phosphoproteomic-based approach, I quantified PI3K downstream phosphorylation-regulated targets in a pancreatic cancer cell line treated or not by a pan- or selective PI3K inhibitor at different times. I demonstrated for the first time existence of targets, signalling pathways and adaptive responses regulated by each PI3K isoform. To conclude, all these results demonstrate the rational of combinatorial use of isoform-specific PI3K inhibitors in patients with pancreatic cancer for better clinical response

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Tyrosine phosphoproteomics of patient-derived xenografts reveals ephrin type-B receptor 4 tyrosine kinase as novel therapeutic target in pancreatic cancer

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