The FGFR4 Y367C mutant is a dominant oncogene in MDA-MB453 breast cancer cells

Roidl, Andreas; Foo, Priscilla; Wong, Wei; Mann, Christian; Bechtold, S; Berger, Hans-Jürgen; Streit, Sylvia; Ruhe, Jens E.; Hart, Stefan; Ullrich, Axel; Ho, Han Kiat

doi:10.1038/onc.2009.432

Cited by 56 publications

(53 citation statements)

References 31 publications

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“…Data generated with breast tumor cell lines displaying FGFR1 (11) or FGFR2 (12, 28) amplification showed that they were very sensitive to treatment with the multitargeted inhibitor PD173074. MDA-MB453 breast tumor cells with the activating FGFR4 Y367C mutation (13) are also very sensitive to PD173074, showing a strong proliferative block following treatment with the inhibitor (28). Moreover, a breast cancer model showing autocrine ligand-mediated FGFR activity was very responsive to TKI168 both in vitro and in vivo (29).…”

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confidence: 88%

“…Whether additional breast cancer patients with activating mutations in FGFR3 will be uncovered, or if this mutation had a causal role in the disease, remains to be studied. Regarding FGFR4, an activating mutation (Y367C) that causes constitutive receptor dimerization was discovered in the MDA-MB453 breast tumor cell line (13). The mutation is in a homologous region to mutations in FGFR2 and FGFR3, which are associated with human diseases.…”

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confidence: 99%

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Potential for Targeting the Fibroblast Growth Factor Receptors in Breast Cancer

Hynes

Dey

2010

Cancer Research

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Breast cancer is the most common cancer of women, accounting yearly for approximately 30% of newly diagnosed cases and ranking second as a cause of death. Despite improvements in breast cancer detection and development of new therapeutic approaches, there are still tumors for which no targeted therapies are available. This review summarizes recent findings on the fibroblast growth factor receptors (FGFR) and the data supporting their role in breast cancer. We will describe the approaches being made to develop therapeutics targeting these receptors. Finally, to improve the chances for success with FGFR signal transduction inhibitors, strategies to choose appropriate breast cancer patients for treatment will be discussed. Cancer Res; 70(13); 5199-202. ©2010 AACR.Breast cancer is a heterogeneous disease, from the cellular morphology to the array of expressed genes in individual tumors. Despite this heterogeneity, there are specific genetic alterations that are found in a relatively high percentage of breast cancers, such as the ERBB2 amplicon on chromosome 17q21 present in approximately 25% of primary tumors. As a transmembrane receptor with kinase activity, ErbB2 has proved to be an excellent target for cancer therapy. Various types of signal transduction inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors (TKI), are used to treat patients whose tumors possess the ERBB2 amplicon and overexpress the receptor (reviewed in ref. 1). Currently much effort is going into targeting additional genetic alterations driving breast cancer. Here, we will discuss the fibroblast growth factor/fibroblast growth factor receptor (FGF/ FGFR) network, whose members have multiple, essential developmental roles and have also been implicated in different types of human tumors, including breast cancer.In mammals, there are four FGFRs that encode transmembrane receptors with tyrosine kinase activity. Furthermore, alternative splicing of FGFR 1, 2, and 3 in the third Ig-like loop domain gives rise to the IIIb and IIIc isoforms, which are expressed in epithelial or mesenchymal compartments, respectively. There are 22 FGF ligands, 18 of which that bind specific FGFR isoforms, inducing receptor dimerization, kinase activation, and autophosphorylation of intracellular tyrosine residues (reviewed in ref.2). In addition to phosphorylation of tyrosine residues on the receptors and on PLCγ, the adaptor protein FRS2 that links FGFRs to the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, is heavily phosphorylated in response to receptor activation. Other effector proteins including STAT transcription factors and Src are also activated by FGFRs (Fig. 1, center Fgf4, Fgf6, Fgf8, Fgf10, and Fgfr2;. In this review we will concentrate on breast cancer, presenting the evidence for FGF/FGFR involvement in human disease and discussing current approaches that might be used for targeting oncogenic FGFRs in breast cancer.Large-scale analyses of human cancer genomes have revealed that FGFRs ...

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Potential for Targeting the Fibroblast Growth Factor Receptors in Breast Cancer

Hynes

Dey

2010

Cancer Research

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“…This may be reconciled by the fact that (1) patients with PIK3CA mutant cancers have a better outcome (Kalinsky et al, 2009) and may be under-represented in the group of patients with metastatic disease, (2) B30% of breast cancers show PTEN protein loss (Hennessy et al, 2005;Perez-Tenorio et al, 2007;Stemke-Hale et al, 2008), which in contrast to PTEN mutations is not mutually exclusive with PIK3CA mutations (Perez-Tenorio et al, 2007;Stemke-Hale et al, 2008) and that (3) MAPK pathway activation due to other genomic/molecular aberrations may not be uncommon (Adelaide et al, 2007;Roidl et al, 2010), which would result in mTOR inhibitor resistance in a subset of PIK3CA-mutated cancers according to our findings. In addition, it has been suggested that the strength of PI3K-AKT pathway activation may differ in vitro compared with human PIK3CA-mutated breast cancer (Loi et al, 2010).…”

Section: Discussionmentioning

confidence: 94%

PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs

2011

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The phosphatidylinositol 3-kinase (PI3K) pathway is commonly activated in breast cancers due to frequent mutations in PIK3CA, loss of expression of PTEN or over-expression of receptor tyrosine kinases. PI3K pathway activation leads to stimulation of the key growth and proliferation regulatory kinase mammalian target of rapamycin (mTOR), which can be inhibited by rapamycin analogues and by kinase inhibitors; the effectiveness of these drugs in breast cancer treatment is currently being tested in clinical trials. To identify the molecular determinants of response to inhibitors that target mTOR via different mechanisms in breast cancer cells, we investigated the effects of pharmacological inhibition of mTOR using the allosteric mTORC1 inhibitor everolimus and the active-site mTORC1/mTORC2 kinase inhibitor PP242 on a panel of 31 breast cancer cell lines. We demonstrate here that breast cancer cells harbouring PIK3CA mutations are selectively sensitive to mTOR allosteric and kinase inhibitors. However, cells with PTEN loss of function are not sensitive to these drugs, suggesting that the functional consequences of these two mechanisms of activation of the mTOR pathway are quite distinct. In addition, a subset of HER2-amplified cell lines showed increased sensitivity to PP242, but not to everolimus, irrespective of the PIK3CA/PTEN status. These selective sensitivities were confirmed in more physiologically relevant three-dimensional cell culture models. Our findings provide a rationale to guide selection of breast cancer patients who may benefit from mTOR inhibitor therapy and highlight the importance of accurately assessing the expression of PTEN protein and not just its mutational status.

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“…Activation of FGFR-dependent signaling pathways can stimulate tumor initiation, progression, and resistance to therapy. Translocation events implicating the FGFR1 gene and various fusions of FGFR1 are found in myeloproliferative syndromes (12); chromosomal translocations of FGFR1 or FGFR3 and the transforming acidic coiled-coil genes (TACC1 or TACC3) are oncogenic in glioblastoma multiforme, bladder cancer, head and neck cancer, and lung cancer (13)(14)(15)(16); oncogenic mutations of FGFR2 and FGFR3 are observed in lung squamous cell carcinoma; FGFR2 N549K is observed in 25% of endometrial cancers; FGFR3 t(4;14) alterations are reported in 15-20% of multiple myeloma (17)(18)(19); FGFR4 Y367C mutation in the transmembrane domain drives constitutive activation and enhanced tumorigenic phenotypes in a breast carcinoma cell line (20)(21)(22); and K535 and E550 mutants are reported to activate FGFR4 in rhabdomyosarcoma (23). FGFR amplification is reported in various cancers (24,25): FGFR1 is amplified in colorectal, lung, and renal cell cancers (26,27); FGFR2 is amplified in gastric cancer and colorectal cancer (28,29); FGFR3 is commonly amplified in bladder cancer and also is reported for cervical, oral, and hematological cancers (30)(31)(32); and FGFR4 is amplified in hepatocellular carcinoma, gastric cancer, pancreatic cancer, and ovarian cancer (33)(34)(35)(36)(37).…”

Section: Significancementioning

confidence: 99%

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Li¹,

Wang²,

Tanizaki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

159

132

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The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.drug discovery | cancer drug resistance | kinase inhibitor | structure-based drug design R eceptor tyrosine kinases (RTKs) serve as critical sensors of extracellular cues that activate a myriad of intracellular signaling pathways to regulate cell state. There are 58 receptor tyrosine kinases in the human genome, and many have been demonstrated to be constitutively activated through amplification or mutation in particular cancers. The signals emanating from these RTKs, such as epidermal growth factor receptor (EGFR), FGF receptor (FGFR), platelet-derived growth factor receptor (PDGFR), protein kinase Kit (KIT), and protein kinase c-Met (MET), have been pharmacologically proven to be essential to the survival of cancers expressing mutant forms of these proteins. However, rapid resistance to monotherapy with first-generation RTK inhibitors has been universally observed. Resistance typically arises from the emergence of cancer cells expressing mutant forms of RTKs that are impervious to the action of first-generation drugs or from the activation of by-pass signaling mechanisms. Resistance can be overcome by developing new inhibitors that target the mutant RTK directly or target bypass signaling mechanisms. Indeed this approach has been deployed succes...

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The FGFR4 Y367C mutant is a dominant oncogene in MDA-MB453 breast cancer cells

Cited by 56 publications

References 31 publications

Potential for Targeting the Fibroblast Growth Factor Receptors in Breast Cancer

Potential for Targeting the Fibroblast Growth Factor Receptors in Breast Cancer

PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

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