Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/30098
Title: Dual targeting of FGFR3 and ERBB3 enhances the efficacy of FGFR inhibitors in FGFR3 fusion-driven bladder cancer.
Austin Authors: Weickhardt, Andrew J ;Lau, David K ;Hodgson-Garms, Margeaux;Lavis, Austen;Jenkins, Laura J;Vukelic, Natalia;Ioannidis, Paul;Luk, Ian Y;Mariadason, John M 
Affiliation: Olivia Newton-John Cancer Wellness and Research Centre
Medical Oncology
Medicine (University of Melbourne)
Olivia Newton-John Cancer Research Institute
School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia
Issue Date: 2-May-2022
Date: 2022
Publication information: BMC Cancer 2022; 22(1): 478
Abstract: Mutations and fusions in Fibroblast Growth Factor Receptor 3 (FGFR3) occur in 10-20% of metastatic urothelial carcinomas and confer sensitivity to FGFR inhibitors. However, responses to these agents are often short-lived due to the development of acquired resistance. The objective of this study was to identify mechanisms of resistance to FGFR inhibitors in two previously uncharacterised bladder cancer cell lines harbouring FGFR3 fusions and assess rational combination therapies to enhance sensitivity to these agents. Acquired resistance to FGFR inhibitors was generated in two FGFR3 fusion harbouring cell lines, SW780 (FGFR3-BAIAP2L1 fusion) and RT4 (FGFR3-TACC3 fusion), by long-term exposure to the FGFR inhibitor BGJ398. Changes in levels of receptor tyrosine kinases were assessed by phospho-RTK arrays and immunoblotting. Changes in cell viability and proliferation were assessed by the Cell-Titre Glo assay and by propidium iodide staining and FACS analysis. Long term treatment of FGFR3-fusion harbouring SW780 and RT4 bladder cancer cell lines with the FGFR inhibitor BGJ398 resulted in the establishment of resistant clones. These clones were cross-resistant to the clinically approved FGFR inhibitor erdafitinib and the covalently binding irreversible FGFR inhibitor TAS-120, but remained sensitive to the MEK inhibitor trametinib, indicating resistance is mediated by alternate activation of MAPK signalling. The FGFR inhibitor-resistant SW780 and RT4 lines displayed increased expression of pERBB3, and strikingly, combination treatment with an FGFR inhibitor and the ATP-competitive pan-ERBB inhibitor AZD8931 overcame this resistance. Notably, rapid induction of pERBB3 and reactivation of pERK also occurred in parental FGFR3 fusion-driven lines within 24 h of FGFR inhibitor treatment, and combination treatment with an FGFR inhibitor and AZD8931 delayed the reactivation of pERBB3 and pERK and synergistically inhibited cell proliferation. We demonstrate that increased expression of pERBB3 is a key mechanism of adaptive resistance to FGFR inhibitors in FGFR3-fusion driven bladder cancers, and that this also occurs rapidly following FGFR inhibitor treatment. Our findings demonstrate that resistance can be overcome by combination treatment with a pan-ERBB inhibitor and suggest that upfront combination treatment with FGFR and pan-ERBB inhibitors warrants further investigation for FGFR3-fusion harbouring bladder cancers.
URI: https://ahro.austin.org.au/austinjspui/handle/1/30098
DOI: 10.1186/s12885-022-09478-4
ORCID: 0000-0001-9218-8669
0000-0002-1003-7478
0000-0001-9123-7684
Journal: BMC Cancer
PubMed URL: 35501832
PubMed URL: https://pubmed.ncbi.nlm.nih.gov/35501832/
Type: Journal Article
Subjects: Acquired resistance
Bladder cancer
EGFR
ERBB2
ERBB3
FGFR3
Targeted therapy
Appears in Collections:Journal articles

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