Highlights • We review the latest data on cellular fibroblast growth factor receptor (FGFR) signalling mechanisms and pathways. • We highlight key roles of FGFR signalling in normal development and ...repair. • We address how, and how often, it can go wrong in development and cancer. • We review the latest data on how FGFR signalling is being targeted therapeutically.
The downregulation of Pleckstrin Homology-Like Domain family A member 1 (PHLDA1) expression mediates resistance to targeted therapies in receptor tyrosine kinase-driven cancers. The restoration and ...maintenance of PHLDA1 levels in cancer cells thus constitutes a potential strategy to circumvent resistance to inhibitors of receptor tyrosine kinases. Through a pharmacological approach, we identify the inhibition of MAPK signalling as a crucial step in
downregulation. Further ChIP-qPCR analysis revealed that MEK1/2 inhibition produces significant epigenetic changes at the
locus, specifically a decrease in the activatory marks H3Kme3 and H3K27ac. In line with this, we show that treatment with the clinically relevant class I histone deacetylase (HDAC) inhibitor 4SC-202 restores PHLDA1 expression in lapatinib-resistant human epidermal growth factor receptor-2 (HER2)
breast cancer cells. Critically, we show that when given in combination, 4SC-202 and lapatinib exert synergistic effects on 2D cell proliferation and colony formation capacity. We therefore propose that co-treatment with 4SC-202 may prolong the clinical efficacy of lapatinib in HER2
breast cancer patients.
FGFR signalling in women's cancers Fearon, Abbie E.; Gould, Charlotte R.; Grose, Richard P.
The international journal of biochemistry & cell biology,
12/2013, Letnik:
45, Številka:
12
Journal Article
Recenzirano
FGFs, in a complex with their receptors (FGFRs) and heparan sulfate (HS), are responsible for a range of cellular functions, from embryogenesis to metabolism. Both germ line and somatic FGFR ...mutations are known to play a role in a range of diseases, most notably craniosynestosis dysplasias, dwarfism and cancer. Because of the ability of FGFR signalling to induce cell proliferation, migration and survival, FGFRs are readily co-opted by cancer cells. Mutations in, and amplifications of, these receptors are found in a range of cancers with some of the most striking clinical findings relating to their contribution to pathogenesis and progression of female cancers. Here, we outline the molecular mechanisms of FGFR signalling and discuss the role of this pathway in women's cancers, focusing on breast, endometrial, ovarian and cervical carcinomas, and their associated preclinical and clinical data. We also address the rationale for therapeutic intervention and the need for FGFR-targeted therapy to selectively target cancer cells in view of the fundamental roles of FGF signalling in normal physiology.
Development of resistance causes failure of drugs targeting receptor tyrosine kinase (RTK) networks and represents a critical challenge for precision medicine. Here, we show that PHLDA1 ...downregulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using fibroblast growth factor receptor (FGFR) inhibition in endometrial cancer cells, we identify an Akt-driven compensatory mechanism underpinned by downregulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 downregulation also occurs in response to RTK-targeted therapy in breast and renal cancer patients, as well as following trastuzumab treatment in HER2+ breast cancer cells. Crucially, knockdown of PHLDA1 alone was sufficient to confer de novo resistance to RTK inhibitors and induction of PHLDA1 expression re-sensitized drug-resistant cancer cells to targeted therapies, identifying PHLDA1 as a biomarker for drug response and highlighting the potential of PHLDA1 reactivation as a means of circumventing drug resistance.
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•The Akt pathway plays a critical role in resistance to tyrosine kinase inhibition•PHLDA1 is key to regulating Akt activity during the development of drug resistance•Knockdown of PHLDA1 alone confers de novo resistance to kinase inhibitors•PHLDA1 rescue resensitizes drug-resistant cancer cells
Fearon et al. use unbiased transcriptomic and phosphoproteomic analysis to identify PHLDA1 as a mediator of acquired resistance to kinase-targeted therapies in cancer. Using a range of cell models and clinical data, they uncover a mechanism underpinning the re-wiring of Akt signaling in cancer drug resistance.
The liver's remarkable regenerative capacity is orchestrated by several growth factors and cytokines. Fibroblast growth factor receptor 3 (Fgfr3) is frequently overexpressed in hepatocellular ...carcinoma and promotes cancer aggressiveness, whereas its role in liver homeostasis, repair and regeneration is unknown. We show here that Fgfr3 is expressed by hepatocytes in the healthy liver. Its major ligand, Fgf9, is mainly expressed by non-parenchymal cells and upregulated upon injury. Mice lacking Fgfr3 in hepatocytes exhibit increased tissue necrosis after acute toxin treatment and more excessive fibrosis after long-term injury. This was not a consequence of immunological alterations in the non-injured liver as revealed by comprehensive flow cytometry analysis. Rather, loss of Fgfr3 altered the expression of metabolic and pro-fibrotic genes in hepatocytes. These results identify a paracrine Fgf9-Fgfr3 signaling pathway that protects from toxin-induced cell death and the resulting liver fibrosis and suggests a potential use of FGFR3 ligands for therapeutic purposes.
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•Fgfr3 is important for hepatocyte survival following CCl4-induced liver injury•Fgfr3 in hepatocytes regulates expression of metabolic and pro-fibrotic genes•Fgfr3 protects from extensive fibrosis after chronic CCl4 treatment•Fgf receptors have unique, but also overlapping functions in hepatocytes
Biological sciences; Cell biology; Molecular biology
Grb-ing receptor activation by the tail Fearon, Abbie E; Grose, Richard P
Nature structural & molecular biology,
02/2014, Letnik:
21, Številka:
2
Journal Article
Recenzirano
Hyperactivation of receptor tyrosine kinase pathways is a common theme in cancer. The recent demonstration that an imbalance between the fibroblast growth factor receptor 2binding proteins Grb2 and ...phospholipase C-1 can lead to invasive behavior in the absence of growth factors highlights an emerging concept in cellular-signaling homeostasis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The downregulation of Pleckstrin Homology-Like Domain family A member 1 (PHLDA1) expression mediates resistance to targeted therapies in receptor tyrosine kinase-driven cancers. The restoration and ...maintenance of PHLDA1 levels in cancer cells thus constitutes a potential strategy to circumvent resistance to inhibitors of receptor tyrosine kinases. Through a pharmacological approach, we identify the inhibition of MAPK signalling as a crucial step in PHLDA1 downregulation. Further ChIP-qPCR analysis revealed that MEK1/2 inhibition produces significant epigenetic changes at the PHLDA1 locus, specifically a decrease in the activatory marks H3Kme3 and H3K27ac. In line with this, we show that treatment with the clinically relevant class I histone deacetylase (HDAC) inhibitor 4SC-202 restores PHLDA1 expression in lapatinib-resistant human epidermal growth factor receptor-2 (HER2)sup.+ breast cancer cells. Critically, we show that when given in combination, 4SC-202 and lapatinib exert synergistic effects on 2D cell proliferation and colony formation capacity. We therefore propose that co-treatment with 4SC-202 may prolong the clinical efficacy of lapatinib in HER2sup.+ breast cancer patients.
Abstract
Background:
Fibroblast growth factors (FGFs) signal by binding to FGF receptors (FGFRs), eliciting a diverse range of cellular responses. FGFR mutations are frequently found in endometrial ...cancer and may be a driving force in tumorigenesis. We are characterizing endometrial cancer cell lines containing common FGFR2 mutations and assessing their effects on cellular transformation.
Methods:
Three endometrial cancer cell lines, containing at least one common FGFR2 mutation, were selected. FGF and FGFR isoform expression and downstream signalling was established using 2D culture and further assessed in a 3D organotypic model.
Immortalized endometrial cells have been generated using a BMI-1 lentivirus. Protein expression and cell behaviour have been characterised and compared to endometrial cancer cells.
FGFR inhibitor treatment and siRNA-mediated FGFR2 knock down in endometrial cancer cells has also been investigated. The effects of these treatments on cell signalling have been assessed using a mass spectrometry (MS) approach, looking at the global downstream phosphoproteome.
The role of FGFR2 mutations in endometrial cancer is being assessed further using a zinc finger nuclease approach. Here, we investigate mutant FGFR2 constructs in immortalized endometrial cells under the control of the endogenous FGFR2 promoter. FGFR2 mutations have also been reversed in endometrial cancer cells and signalling impact assessed using MS.
Results:
FGFR2c and its ligand, FGF2, were expressed strongly in all cell lines. ERK phosphorylation increased upon stimulation with FGF2, indicative of MAP Kinase pathway activation. This was abolished by an FGFR inhibitor. Treatment with FGF7, specific to FGFR2b, had no effect on ERK phosphorylation. AKT phosphorylation remained at basal levels throughout stimulation assays. FGFR inhibitor treatment did not decrease levels of p-AKT.
3D culture data indicate endometrial cancer cells do not invade into the stroma. FGFR inhibitor treatment has cell line specific effects; MFE-296 cells acquire resistance to FGFR inhibition over time, while treatment of AN3CA cells leads to cell death.
Conclusions:
High levels of FGFR2c in these epithelial cell lines indicates receptor class switch from FGFR2b, resulting in increased proliferation and survival, perhaps via autocrine stimulation. Endometrial cancer cells signal via both MAPK and AKT pathways with MAPK predominating when the FGFR pathway is stimulated.
Results of 2D proliferation assays, taken with results of the 3D culture model, indicate: i. MFE-296 cells are sensitive to FGFR inhibition initially but acquire resistance to FGFR inhibitor treatment over prolonged exposure, ii. AN3CA cells are oncogene addicted; inhibition of FGFR2 leads to cell death.
Acknowledgments:
We thank Cancer Research UK for funding.
Citation Format: Abbie E. Fearon, Pedro R. Cutillas, Richard P. Grose. Investigating the functional effects of oncogenic FGFR2 mutations in endometrial cancer. abstract. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4266. doi:10.1158/1538-7445.AM2013-4266
Background: Finger and hand prints are formed during the late first and second trimester of foetal development, after which they remain unchanged. Their expression may be influenced by both genetic ...and environmental factors. Some studies have suggested that a reduced total finger ridge count (TFRC) and, in particular, a reduce total a–b ridge count (TABRC), may be associated with schizophrenia.
Aim: To study these two variables in a large, ethnically homogenous sample and to compare our findings with those of other recent studies.
Method: Finger and hand prints of 150 people with DSM-III-R schizophrenia were compared with those of 92 healthy controls.
Results: Patients had a reduced mean TABRC (
P=0.03) compared with controls. There was a significant (
P=0.02) linear trend for lower TABRC and increasing incidence of schizophrenia
(
OR
linear
trend
=1.3
;
95%
CI
1.1–1.7)
, implying a continuous increase in the risk for schizophrenia with reduction in TABRC. No significant difference between groups was observed for TFRC.
Conclusion: These results provide further evidence that dermatoglyphic abnormalities exist in at least some patients with schizophrenia and that the a–b ridge count may be a marker of disruption, probably environmental, that occurs when the developing brain may also be particularly vulnerable to such insult. These findings support the concept that some cases of schizophrenia may be due to adverse intrauterine events.
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