Potent, Selective Inhibitors of Fibroblast Growth Factor Receptor Define Fibroblast Growth Factor Dependence in Preclinical Cancer Models

Squires, Matthew; Ward, George A.; Saxty, Gordan; Berdini, Valério; Cleasby, Anne; King, Peter; Angibaud, Patrick; Perera, Tim; Fazal, Lynsey; Ross, Douglas D.; Jones, Charlotte Griffiths; Madin, Andrew; Benning, Rajdeep K.; Vickerstaffe, Emma; O’Brien, Alistair; Frederickson, Martyn; Reader, Michael; Hamlett, C.C.F.; Batey, Michael A.; Rich, Sharna J.; Carr, Maria E.; Miller, Darcey; Feltell, Ruth E.; Thiru, Abarna; Bethell, Susanne; Devine, Lindsay A.; Graham, Brent; Pike, Andrew R.; Cosme, José; Lewis, Edward J.; Freyne, Eddy; Lyons, John F.; Irving, Julie; Murray, Christopher W.; Newell, David R.; Thompson, Neil T.

doi:10.1158/1535-7163.mct-11-0426

Cited by 30 publications

(22 citation statements)

References 33 publications

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“…Similar results have been reported for other novel FGFRi. 43 The reduced sensitivity of KMS-18 cells agrees with previous reports wherein FGFR G384D failed to transform NIH3T3 cells 20 and KMS-18 were less sensitive to the TKI CHIR-258/dovitinib. 44 Clearly, FGFR3 mutations are graded in terms of their activation capability and this determines the degree of addiction and sensitivity to FGFRi.…”

Section: Discussionsupporting

confidence: 89%

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

et al. 2012

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Fibroblast growth factor receptors (FGFRs) can act as driving oncoproteins in certain cancers, making them attractive drug targets. Here we have characterized tumour cell responses to two new inhibitors of FGFR1-3, AZ12908010 and the clinical candidate AZD4547, making comparisons with the well-characterized FGFR inhibitor PD173074. In a panel of 16 human tumour cell lines, the anti-proliferative activity of AZ12908010 or AZD4547 was strongly linked to the presence of deregulated FGFR signalling, indicating that addiction to deregulated FGFRs provides a therapeutic opportunity for selective intervention. Acquired resistance to targeted tyrosine kinase inhibitors is a growing problem in the clinic but has not yet been explored for FGFR inhibitors. To assess how FGFRdependent tumour cells adapt to long-term FGFR inhibition, we generated a derivative of the KMS-11 myeloma cell line (FGFR Y373C ) with acquired resistance to AZ12908010 (KMS-11R cells). Basal phosphorylated FGFR and FGFR-dependent downstream signalling were constitutively elevated and refractory to drug in KMS-11R cells. Sequencing of FGFR3 in KMS-11R cells revealed the presence of a heterozygous mutation at the gatekeeper residue, encoding FGFR3 V555M ; consistent with this, KMS-11R cells were crossresistant to AZD4547 and PD173074. These results define the selectivity and efficacy of two new FGFR inhibitors and identify a secondary gatekeeper mutation as a mechanism of acquired resistance to FGFR inhibitors that should be anticipated as clinical evaluation proceeds.

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Section: Discussionsupporting

confidence: 89%

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

et al. 2012

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“…21). GFP-TEL-FGFR1 and GFP-TEL-KDR(VEGFR2) were kindly provided by Jan Cools (Department of Human Genetics, University of Leuven).…”

Section: Cellular Kinase Assaysmentioning

confidence: 99%

Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor

Perera

Jovcheva

Mévellec

et al. 2017

Molecular Cancer Therapeutics

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Fibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links to several hallmarks of cancer. Genetic alterations in FGF receptor (FGFR) family members are associated with increased tumor growth, metastasis, angiogenesis, and decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases. JNJ-42756493 shows rapid uptake into the lysosomal compartment of cells in culture, which is associated with prolonged inhibition of FGFR signaling, possibly due to sustained release of the inhibitor. In xenografts from human tumor cell lines or patient-derived tumor tissue with activating FGFR alterations, JNJ-42756493 administration results in potent and dose-dependent antitumor activity accompanied by pharmacodynamic modulation of phospho-FGFR and phospho-ERK in tumors. The results of the current study provide a strong rationale for the clinical investigation of JNJ-42756493 in patients with tumors harboring FGFR pathway alterations.

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“…We first determined half-maximal inhibitory concentrations (GI 50 values) of the FGFR1-amplified, FGFR inhibitor-sensitive cell lines H1581 and DMS114 against three selective and potent FGFR inhibitors, AZD4542, BGJ398, and JNJ-42756493 (5,(18)(19)(20). Confirming earlier observations, both cell lines were highly sensitive to FGFR inhibition with GI 50 values in the range of 2 to 20 nmol/L and 50 to 300 nmol/L for the H1581 and DMS114 cell lines, respectively (Fig.…”

Section: A Subclonal Population Of Fgfr Inhibitor-resistant Cellsmentioning

confidence: 99%

“…S5A). We performed comprehensive tumor genome characterization using NEO comprehensive genomic sequencing technology on a tumor biopsy taken before initiation of anti-FGFR therapy (5,8,(18)(19)(20)23). We detected a TP53 (p.R248L) mutation and a CDKN2A (p.G23fs) frame-shift mutation.…”

Section: Met Activation In a Patient Relapsing After Initial Responsementioning

confidence: 99%

Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer

Malchers

Ercanoglu

Schütte

et al. 2017

Clinical Cancer Research

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Purpose: The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 11% of such FGFR1-amplified tumors respond to single-agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells.Experimental Design: To investigate possible mechanisms of resistance to FGFR inhibition, we studied the lung cancer cell lines DMS114 and H1581. Both cell lines are highly sensitive to three different FGFR inhibitors, but exhibit sustained residual cellular viability under treatment, indicating a subpopulation of existing drug-resistant cells. We isolated these subpopulations by treating the cells with constant high doses of FGFR inhibitors.Results: The FGFR inhibitor-resistant cells were cross-resistant and characterized by sustained MAPK pathway activation. In drug-resistant H1581 cells, we identified NRAS amplification and DUSP6 deletion, leading to MAPK pathway reactivation. Furthermore, we detected subclonal NRAS amplifications in 3 of 20 (15%) primary human FGFR1-amplified SQLC specimens. In contrast, drug-resistant DMS114 cells exhibited transcriptional upregulation of MET that drove MAPK pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors.Conclusions: We provide evidence for the existence of diverse mechanisms of primary drug resistance in FGFR1-amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment.

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Potent, Selective Inhibitors of Fibroblast Growth Factor Receptor Define Fibroblast Growth Factor Dependence in Preclinical Cancer Models

Cited by 30 publications

References 33 publications

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

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

Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor

Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer

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