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Targeting FGFRs Using PD173074 as a Novel Therapeutic Strategy in Cholangiocarcinoma

Balasubramanian, Brinda; Yacqub-Usman, Kiren; Venkatraman, Simran; Myint, Kyaw Zwar; Juengsamarn, Jitlada; Sarkhampee, Poowanai; Lertsawatvicha, Nithi; Sripa, Jittiyawadee; Kuakpaetoon, Thiti; Suriyonplengsaeng, Chinnawut; Wongprasert, Kanokpan; Grabowska, Anna M.; Bates, David O.; Janvilisri, Tavan; Tohtong, Rutaiwan

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Authors

Kiren Yacqub-Usman

Simran Venkatraman

Kyaw Zwar Myint

Jitlada Juengsamarn

Poowanai Sarkhampee

Nithi Lertsawatvicha

Jittiyawadee Sripa

Thiti Kuakpaetoon

Chinnawut Suriyonplengsaeng

Kanokpan Wongprasert

Anna M. Grabowska

Tavan Janvilisri

Rutaiwan Tohtong



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.

Citation

Balasubramanian, B., Yacqub-Usman, K., Venkatraman, S., Myint, K. Z., Juengsamarn, J., Sarkhampee, P., Lertsawatvicha, N., Sripa, J., Kuakpaetoon, T., Suriyonplengsaeng, C., Wongprasert, K., Grabowska, A. M., Bates, D. O., Janvilisri, T., & Tohtong, R. (2023). Targeting FGFRs Using PD173074 as a Novel Therapeutic Strategy in Cholangiocarcinoma. Cancers, 15(9), Article 2528. https://doi.org/10.3390/cancers15092528

Journal Article Type Article
Acceptance Date Apr 27, 2023
Online Publication Date Apr 28, 2023
Publication Date May 1, 2023
Deposit Date May 9, 2023
Publicly Available Date May 11, 2023
Journal Cancers
Electronic ISSN 2072-6694
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 15
Issue 9
Article Number 2528
DOI https://doi.org/10.3390/cancers15092528
Keywords FGFR inhibitors; cholangiocarcinoma; biliary tract cancer; molecular targeted therapy; therapeutic biomarker; precision medicine
Public URL https://nottingham-repository.worktribe.com/output/20287353
Publisher URL https://www.mdpi.com/2072-6694/15/9

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