Targeting FGFRs Using PD173074 as a Novel Therapeutic Strategy in Cholangiocarcinoma
Author:
Balasubramanian Brinda1ORCID, Yacqub-Usman Kiren2ORCID, Venkatraman Simran3ORCID, Myint Kyaw Zwar3, Juengsamarn Jitlada4, Sarkhampee Poowanai5, Lertsawatvicha Nithi5, Sripa Jittiyawadee6, Kuakpaetoon Thiti7, Suriyonplengsaeng Chinnawut8, Wongprasert Kanokpan8ORCID, Grabowska Anna M.2ORCID, Bates David O.2ORCID, Janvilisri Tavan13ORCID, Tohtong Rutaiwan1ORCID
Affiliation:
1. Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand 2. Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK 3. Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok 10400, Thailand 4. Oncology Unit, Department of Medicine, Sunpasitthiprasong Hospital, Ubon Ratchathani 34000, Thailand 5. General Surgery Division, Department of Surgery, Sanpasitthiprasong Hospital, Ubon Ratchathani 34000, Thailand 6. College of Medicine and Public Health, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand 7. Department of Pathology, Rajavithi Hospital, Bangkok 10400, Thailand 8. Department of Anatomy, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
Abstract
Cholangiocarcinoma (CCA) is an architecturally complex tumour with high heterogeneity. Discovery at later stages makes treatment challenging. However, the lack of early detection methodologies and the asymptomatic nature of CCA make early diagnosis more difficult. Recent studies revealed the fusions in Fibroblast Growth Factor Receptors (FGFRs), a sub-family of RTKs, as promising targets for targeted therapy for CCA. Particularly, FGFR2 fusions have been of particular interest, as translocations have been found in approximately 13% of CCA patients. Pursuing this, Pemigatinib, a small-molecule inhibitor of FGFR, became the first targeted therapy drug to be granted accelerated approval by the FDA for treating CCA patients harbouring FGFR2 fusions who have failed first-line chemotherapy. However, despite the availability of Pemigatinib, a very limited group of patients benefit from this treatment. Moreover, as the underlying mechanism of FGFR signalling is poorly elucidated in CCA, therapeutic inhibitors designed to inhibit this pathway are prone to primary and acquired resistance, as witnessed amongst other Tyrosine Kinase Inhibitors (TKIs). While acknowledging the limited cohort that benefits from FGFR inhibitors, and the poorly elucidated mechanism of the FGFR pathway, we sought to characterise the potential of FGFR inhibitors in CCA patients without FGFR2 fusions. Here we demonstrate aberrant FGFR expression in CCA samples using bioinformatics and further confirm phosphorylated-FGFR expression in paraffinised CCA tissues using immunohistochemistry. Our results highlight p-FGFR as a biomarker to guide FGFR-targeted therapies. Furthermore, CCA cell lines with FGFR expression were sensitive to a selective pan-FGFR inhibitor, PD173074, suggesting that this drug can be used to suppress CCA cells irrespective of the FGFR2 fusions. Finally, the correlation analysis utilising publicly available cohorts suggested the possibility of crosstalk amongst the FGFR and EGFR family of receptors as they are significantly co-expressed. Accordingly, dual inhibition of FGFRs and EGFR by PD173074 and EGFR inhibitor erlotinib was synergistic in CCA. Hence, the findings from this study provide support for further clinical investigation of PD173074, as well as other FGFR inhibitors, to benefit a larger cohort of patients. Altogether, this study shows for the first time the potential of FGFRs and the importance of dual inhibition as a novel therapeutic strategy in CCA.
Funder
Mahidol University
Subject
Cancer Research,Oncology
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