Tumour cell responses to new fibroblast growth factor receptor tyrosine kinase inhibitors and identification of a gatekeeper mutation in FGFR3 as a mechanism of acquired resistance

Chell, Victoria; Balmanno, Kathryn; Little, Annette S.; Wilson, Michael; Andrews, Simon; Blockley, Laura; Hampson, Mark; Gavine, Paul R.; Cook, Simon J.

doi:10.1038/onc.2012.319

Cited by 133 publications

(122 citation statements)

References 58 publications

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“…3A). Gatekeeper mutations which impair drug binding in the ATP-binding pocket of FGFR were previously identified as a mechanism of resistance in cell linebased assays (29,30). Consistent with this, we observed the emergence of a FGFR2 V565F gatekeeper mutation in GAGA6-R þ -resistant cells (Fig.…”

Section: Azd4547 Resistance In Cell Culture-derived (Gaga6-r þ ) and supporting

confidence: 75%

“…In contrast to cell line-based studies (29), GAGA6 PDX tumors that were under continuous AZD4547 treatment in vivo did not develop gatekeeper mutations in the ATP-binding pocket of FGFR2. The lack of gatekeeper mutations in AZD4547-resistant cells was also observed in another FGFR2-amplified PDX, GAGA3, when subjected to AZD4547 selection in vivo (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 60%

“…In a recent study, the acquisition of a gatekeeper mutation, p.V564F, in FGFR2 was found to confer resistance in three cholangiocarcinoma patients with acquired clinical resistance to BGJ398 (43). This study highlights the first clinical occurrence of the FGFR2 V564F gatekeeper mutation as a mechanism of acquired resistance, which had been previously investigated in preclinical studies (28,29). In gastric cancer, clinical resistance to FGFR inhibitors has not been well reported, and our understanding of acquired resistance mechanisms is limited.…”

Section: Discussionmentioning

confidence: 87%

“…Current efforts to understand FGFR inhibitor resistance have focused on in vitro cell line modeling, and gatekeeper mutations in the kinase domain of many FGFRs have been reported as a mechanism for acquired drug resistance; however, it is not known whether these findings are clinically relevant (28,29).…”

Section: Azd4547 Resistance In Cell Culture-derived (Gaga6-r þ ) and mentioning

confidence: 99%

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Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β

Lau

Teng

Huang

et al. 2018

Molecular Cancer Therapeutics

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Preclinical models of diffuse-type gastric cancer (DGC) that reliably predict clinical activity of novel compounds are lacking. To overcome the problem of poor tumor cellularity in DGC, we used cells from malignant ascites to establish DGC patientderived xenograft (PDX) models that recapitulate the primary cancer. Cells in PDX model GAGA6 with FGFR2 amplification were sensitive to AZD4547, a potent FGFR inhibitor that is being clinically evaluated for FGFR-aberrant cancer types. Intermittent in vivo treatment of GAGA6 tumors with AZD4547 gave rise to PDX tumors with acquired resistance to AZD4547, GAGA6-R. Surprisingly, there were no mutations in the FGFR2 gene in GAGA6-R, negating gatekeeper mutations as a mechanism of drug resistance. Phosphorylation of FGFR2 and downstream signaling molecules AKT/PKB and MAPK/ERK remained inhibited by AZD4547. Further analysis of signaling pathways identified AKT-independent phosphorylation and inhibition of GSK3b as a mechanism of drug resistance in GAGA6-R cells. Treatment of GAGA6-R cells with protein kinase C (PKC) inhibitor H7 in combination with AZD4547 led to dephosphorylation and activation of GSK3b with concomitant downregulation of MCL-1 and BCL-XL. Combined treatment with AZD4547 and H7 in vitro synergistically enhanced cell death in GAGA6-R but not GAGA6 cells. Furthermore, midostaurin, a multikinase inhibitor with PKC-inhibiting activity, in part reversed resistance of GAGA6-R tumor to AZD4547 in vivo. Our results suggest that upon challenge with FGFR inhibitors, FGFR2-amplified tumors that are highly dependent on FGFR2 signaling for survival rapidly develop resistance by switching to a PKC-mediated inhibition of GSK3b to gain a survival advantage.

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Section: Azd4547 Resistance In Cell Culture-derived (Gaga6-r þ ) and supporting

confidence: 75%

Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 87%

Section: Azd4547 Resistance In Cell Culture-derived (Gaga6-r þ ) and mentioning

confidence: 99%

See 2 more Smart Citations

Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β

Lau

Teng

Huang

et al. 2018

Molecular Cancer Therapeutics

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“…However, several preclinical models have pointed to possible mechanisms of resistance against FGFR therapies. In MM cell lines, a gatekeeper mutation in FGFR3 (FGFR3 V555M) is involved in resistance to AZD4547 and PD173074 (both Pan-FGFR Inhibitors) (Chell et al, 2013). In endometrial cell lines, several FGFR2 point mutations (especially V564I) have been reported to confer different degrees of resistance to multi-target inhibitors (Dovitinib, Ponatinib and PD173074) (Byron et al, 2013).…”

Section: Resistance To Therapiesmentioning

confidence: 99%

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

179

162

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Introduction The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. Areas Covered This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Expert opinion Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations

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Bcl‐2 inhibitors enhance FGFR inhibitor‐induced mitochondrial‐dependent cell death in FGFR2‐mutant endometrial cancer

et al. 2019

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Endometrial cancer is the most commonly diagnosed gynaecological malignancy. Unfortunately, 15–20% of women demonstrate persistent or recurrent tumours that are refractory to current chemotherapies. We previously identified activating mutations in fibroblast growth factor receptor 2 ( FGFR 2) in 12% (stage I/ II ) to 17% (stage III / IV ) endometrioid EC s and found that these mutations are associated with shorter progression‐free and cancer‐specific survival. Although FGFR inhibitors are undergoing clinical trials for treatment of several cancer types, little is known about the mechanism by which they induce cell death. We show that treatment with BGJ 398, AZD 4547 and PD 173074 causes mitochondrial depolarization, cytochrome c release and impaired mitochondrial respiration in two FGFR 2‐mutant EC cell lines ( AN 3 CA and JHUEM 2). Despite this mitochondrial dysfunction, we were unable to detect caspase activation following FGFR inhibition; in addition, the pan‐caspase inhibitor Z‐ VAD ‐ FMK was unable to prevent cell death, suggesting that the cell death is caspase‐independent. Furthermore, while FGFR inhibition led to an increase in LC 3 puncta, treatment with bafilomycin did not further increase lipidated LC 3, suggesting that FGFR inhibition led to a block in autophagosome degradation. We confirmed that cell death is mitochondrial‐dependent as it can be blocked by overexpression of Bcl‐2 and/or Bcl‐ XL . Importantly, we show that combining FGFR inhibitors with the BH 3 mimetics ABT 737/ ABT 263 markedly increased cell death in vitro and is more effective than BGJ 398 alone in vivo , where it leads to marked tumour regression. This work may have implications for the design of clinical trials to treat a wide range of patients with FGFR ‐dependent malignancies.

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Tumour cell responses to new fibroblast growth factor receptor tyrosine kinase inhibitors and identification of a gatekeeper mutation in FGFR3 as a mechanism of acquired resistance

Cited by 133 publications

References 58 publications

Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β

Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Bcl‐2 inhibitors enhance FGFR inhibitor‐induced mitochondrial‐dependent cell death in FGFR2‐mutant endometrial cancer

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