Dissecting FGF Signalling to Target Cellular Crosstalk in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a 5 year survival rate of less than 8%, and is predicted to become the second leading cause of cancer-related death by 2030. Alongside late detection, which impacts upon surgical treatment, PDAC tumours are challenging to treat due to their desmoplastic stroma and hypovascular nature, which limits the effectiveness of chemotherapy and radiotherapy. Pancreatic stellate cells (PSCs), which form a key part of this stroma, become activated in response to tumour development, entering into cross-talk with cancer cells to induce tumour cell proliferation and invasion, leading to metastatic spread. We and others have shown that Fibroblast Growth Factor Receptor (FGFR) signalling can play a critical role in the interactions between PDAC cells and the tumour microenvironment, but it is clear that the FGFR signalling pathway is not acting in isolation. Here we describe our current understanding of the mechanisms by which FGFR signalling contributes to PDAC progression, focusing on its interaction with other pathways in signalling networks and discussing the therapeutic approaches that are being developed to try and improve prognosis for this terrible disease.

The Role of Feedback Loops in Targeted Therapy for Pancreatic Cancer

“…There were two main types of targeted drugs for FGFR. One was multi-tyrosine kinase inhibitors, which mainly included Ponatinib, Dovitinib, and nintedanib; the other was FGFR selective inhibitors, which mainly included PD173074, AZD4547, and BGJ398 ( 89 ). At present, these drugs had entered clinical or preclinical studies, and it was conceivable that targeting and interfering with the FGFR loop would benefit pancreatic cancer patients.…”

The FGFR2c/PKCε Axis Controls MCL-1-Mediated Invasion in Pancreatic Ductal Adenocarcinoma Cells: Perspectives for Innovative Target Therapies

“…As mentioned above, the desmoplastic stroma is a typical feature of PDAC [ 10 , 11 ], in which the dysregulated signaling of several mitogenic growth factors, such as Epithelial Growth Factor (EGF), Insuline-Like Growth Factor (IGF), Platelet-Derived Growth Factor (PDGF) and Vascular-Endothelial Growth Factor (VEGF) appear to play important roles [ 1 ]. Among them, Fibroblast Growth Factor (FGF) is increasingly recognized as critical player in tumor/stroma cell crosstalk, pointing to the FGF/FGFR axis as a suitable target for combined therapies [ 12 ]. PDAC-derived tissues and cell lines display different patterns and amounts of the four FGFR family members, with FGFR1 and FGFR2 appearing the most involved in oncogenesis and FGFR4 playing an opposite tumor-suppressive function [ 12 ].…”

Roles of the FGF-FGFR Signaling System in Cancer Development and Inflammation

“…The Special Issue contains 13 articles consisting of 3 original articles and 10 review articles that cover a broad spectrum of the involvement of the FGFs-FGFRs in malignant transformation and inflammation. Various aspects of FGF-FGFR signaling and downstream partners in several types of cancer such as breast cancer [ 9 , 10 ], pancreatic cancer [ 11 ], GIST and soft tissue sarcomas [ 12 ] are discussed. In addition, more general mechanisms of FGF-FGFR signaling in cancer including negative regulation of signaling [ 13 ], noncanonical FGF/FGFR binding partners in cancer [ 14 ] and role of oncogenic fusion proteins in centrosome and cilia formation [ 15 ] are presented.…”

“…The Special Issue also contains review articles summarizing the current state of knowledge on the involvement of FGF/FGFR in specific forms of cancer, such as lung cancer [ 21 ], pancreatic cancer [ 11 ], sarcomas, [ 12 ] and breast cancer [ 10 ]. In some subgroups of lung cancer (small-cell lung cancer, non-small-cell lung cancer and squamous cell carcinoma) the incidence reaches 6–22%.…”

“…Carter et al [ 11 ] review the role of FGFR signaling in the progression of pancreatic ductal adenocarcinoma (PDAC). PDAC is the most lethal form of pancreatic cancer and new specific diagnostic methods and more effective therapies are needed.…”