Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1–3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with<i>FGFR3</i>Alterations

Pal, Sumanta K.; Rosenberg, Jonathan E.; Hoffman-Censits, Jean H.; Berger, Raanan; Quinn, David I.; Galsky, Matthew D.; Wolf, Juergen; Dittrich, Christian; Keam, Bhumsuk; Delord, Jean Pierre; Schellens, Jan H.M.; Gravis, Gwénaëlle; Médioni, Jacques; Maroto, Pablo; Sriuranpong, Virote; Charoentum, Chaiyut; Burris, Howard A.; Grünwald, Viktor; Petrylak, Daniel P.; Vaishampayan, Ulka N.; Gez, Eliahu; Giorgi, Ugo De; Lee, Jae‐Lyun; Voortman, Jens; Gupta, Sumati; Sharma, Sunil; Mortazavi, Amir; Vaughn, David J.; Isaacs, Randi; Parker, Kathy P.; Chen, Xueying; Yu, Kun; Porter, Dale; Porta, Diana Graus; Bajorin, Dean F.

doi:10.1158/2159-8290.cd-18-0229

Cited by 219 publications

(170 citation statements)

References 32 publications

(37 reference statements)

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“…These novel findings can give insight in tumor development, as aberrant FGFR1 regulation is important in a wide variety of cancers [12,17] . FGFR inhibitors are already being used in clinical trials as novel anti-cancer drugs [18][19][20][21][22][23] . Our study opens up new potential targets for FGFR1 regulation in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, increased expression of FGFR's has been correlated with a bad prognosis, increased metastasis and tumor progression in a large variety of cancers [13][14][15][16][17] . Indeed, animal studies and clinical trials are currently ongoing to test the effects of FGFR inhibitors on cancer treatment, showing promising initial results [18][19][20][21][22][23] . This highlights the importance of understanding how FGFR expression is regulated.…”

Section: Introductionmentioning

confidence: 99%

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Mechanosensitive regulation of FGFR1 through the MRTF-SRF pathway

Zonderland

Rezzola

Moroni

2019

Preprint

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Controlling basic fibroblast growth factor (bFGF) signaling is important for both tissueengineering purposes, controlling proliferation and differentiation potential, and for cancer biology, influencing tumor progression and metastasis. Here, we observed that human mesenchymal stromal cells (hMSCs) no longer responded to soluble or covalently bound bFGF when cultured on microfibrillar substrates, while fibroblasts did. This correlated with a downregulation of FGF receptor 1 (FGFR1) expression of hMSCs on microfibrillar substrates, compared to hMSCs on conventional tissue culture plastic (TCP). hMSCs also expressed less SRF on ESP scaffolds, compared to TCP, while fibroblasts maintained high FGFR1 and SRF expression. Inhibition of actin-myosin tension or the MRTF/SRF pathway decreased FGFR1 expression in hMSCs, fibroblasts and MG63 osteosarcoma cells. This downregulation was functional, as hMSCs became irresponsive to bFGF in the presence of MRTF/SRF inhibitor. Together, our data show that hMSCs, but not fibroblasts, are irresponsive to bFGF when cultured on microfibrillar susbtrates by downregulation of FGFR1 through the MRTF/SRF pathway. This is the first time FGFR1 expression has been shown to be mechanosensitive and adds to the sparse literature on FGFR1 regulation. These results could open up new targets for cancer treatments and could aid designing tissue engineering constructs that better control cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanosensitive regulation of FGFR1 through the MRTF-SRF pathway

Zonderland

Rezzola

Moroni

2019

Preprint

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“…Similarly, Pal et al, reported that only 42.9% of patients with documented FGFR3 activating point mutations responded to infigratinib (14,15). These results indicate that notwithstanding the presence of a FGFR3 molecular alteration, there remains a significant proportion of patients that harbour intrinsic resistance to selective FGFR TKIs and do not respond to these agents.…”

Section: Introductionmentioning

confidence: 92%

“…The most advanced candidates include erdafitinib (JNJ-42756493) and infigratinib (BGJ398). Pal et al, reported response rates of 25.4% in the evaluation of infigratinib in 67 patients with previously treated advanced urothelial carcinoma with FGFR3 alterations (14). Similarly, the BLC2001 phase II single-arm trial of erdafitinib in FGFR-altered urothelial carcinomas showed clinical responses in 40% of patients (15).…”

Section: Introductionmentioning

confidence: 99%

Targeting the Src pathway enhances the efficacy of selective FGFR inhibitors in cancers with FGFR3 alterations

Lima

Atkinson

Bunney

et al. 2020

Preprint

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Selective FGFR inhibitors such as infigratinib (BGJ398) and erdafitinib (JNJ-42756493) have been evaluated in clinical trials for cancers with FGFR3 molecular alterations, particularly in urothelial carcinoma patients. However, a substantial proportion of these patients (up to 50%) display intrinsic resistance to these drugs and receive minimal clinical benefit. There is thus an unmet need for alternative therapeutic strategies to overcome primary resistance to selective FGFR inhibitors. In this study, we demonstrate that cells expressing cancerassociated activating FGFR3 mutants and the FGFR3-TACC3 fusion showed primary resistance to infigratinib in long-term colony formation assays in both NIH-3T3 and urothelial carcinoma models. We find that expression of these FGFR3 molecular alterations resulted in elevated constitutive Src activation compared to wildtype FGFR3 and that cells co-opted this pathway as a means to achieve intrinsic resistance to infigratinib. Targeting the Src pathway with low doses of the kinase inhibitor dasatinib synergistically sensitized multiple urothelial carcinoma lines harbouring endogenous FGFR3 alterations to infigratinib. Our preclinical data provides evidence that supports the use of dasatinib in combination with selective FGFR inhibitors as a means to overcome intrinsic drug resistance in the salvage therapy setting in cancer patients with FGFR3 molecular alterations.

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“…To confirm these results, we assessed the potential antiproliferative effects of other FGFR inhibitors: NVP-BGJ398 [63], ponatinib [64] and dovitinib [65]. GBS6 cells were incubated with increasing concentrations of NVP-BGJ398, ponatinib, or dovitinib.…”

Section: Ews-oct-4 Induces Transcriptional Activation Of the Fgf-4 Enmentioning

confidence: 97%

Critical role of the fibroblast growth factor signalling pathway in Ewing's sarcoma octamer‐binding transcription factor 4‐mediated cell proliferation and tumorigenesis

Kim

Shim

et al. 2019

The FEBS Journal

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Certain bone and soft tissue (BST) tumours harbour a chromosomal translocation [t(6;22)(p21;q12)], which fuses the Ewing's sarcoma (EWS) gene at 22q12 with the octamer‐binding transcription factor 4 (Oct‐4) gene at 6p21, resulting in the chimeric EWS‐Oct‐4 protein that possesses high transactivation ability. Although abnormal activation of signalling pathways can lead to human cancer development, the pathways underlying these processes in human BST tumours remain poorly explored. Here, we investigated the functional significance of fibroblast growth factor (FGF) signalling in human BST tumours. To identify the gene(s) involved in the FGF signalling pathway and potentially regulated by EWS‐Oct‐4 (also called EWS‐POU5F1), we performed RNA‐Seq analysis, electrophoretic mobility shift assays, chromatin immunoprecipitation assays, and xenograft assays. Treating GBS6 or ZHBTc4 cells‐expressing EWS‐Oct‐4 with the small molecule FGF receptor (FGFR) inhibitors PD173074, NVPBGJ398, ponatinib, and dovitinib suppressed cellular proliferation. Gene expression analysis revealed that, among 22 Fgf and four Fgfr family members, Fgf‐4 showed the highest upregulation (by 145‐fold) in ZHBTc4 cells‐expressing EWS‐Oct‐4. Computer‐assisted analysis identified a putative EWS‐Oct‐4‐binding site at +3017/+3024, suggesting that EWS‐Oct‐4 regulates Fgf‐4 expression in human BST tumours. Fgf‐4 enhancer constructs showed that EWS‐Oct‐4 transactivated the Fgf‐4 gene reporter in vitro, and that overexpression of EWS‐Oct‐4 stimulated endogenous Fgf‐4 gene expression in vivo. Finally, PD173074 significantly decreased tumour volume in mice. Taken together, these data suggest that FGF‐4 signalling is involved in EWS‐Oct‐4‐mediated tumorigenesis, and that its inhibition impairs tumour growth in vivo significantly.

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Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1–3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma withFGFR3Alterations

Cited by 219 publications

References 32 publications

Mechanosensitive regulation of FGFR1 through the MRTF-SRF pathway

Mechanosensitive regulation of FGFR1 through the MRTF-SRF pathway

Targeting the Src pathway enhances the efficacy of selective FGFR inhibitors in cancers with FGFR3 alterations

Critical role of the fibroblast growth factor signalling pathway in Ewing's sarcoma octamer‐binding transcription factor 4‐mediated cell proliferation and tumorigenesis

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