FAK signaling in human cancer as a target for therapeutics

Lee, Brian Y.; Timpson, Paul; Horvath, Lisa G.; Daly, Roger J.

doi:10.1016/j.pharmthera.2014.10.001

Cited by 350 publications

(349 citation statements)

References 259 publications

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“…Consistent with this idea, Ret expression leads to both Src42A and Fak phosphorylation, but we find that the two kinases have opposing effects on proliferation: Src42A promotes proliferation downstream of Ret, whereas Fak blocks it. Hence, despite the fact that blocking Fak function may represent a therapeutic opportunity in some cancers (Ashton et al , 2010; Lee et al , 2015), our findings are more aligned with a previous study (Macagno et al , 2014) that suggested that, at least in the context of Ret‐driven tumorigenesis, Fak can act as a tumour suppressor. In future, it will also be of interest to explore how the Ras/Raf/Erk pathway, activated by Ret in other contexts and previously shown to affect ISC proliferation in flies (Buchon et al , 2010; Biteau & Jasper, 2011; Jiang et al , 2011), intersects with Src/Fak/Wg signalling in response to Ret activation.…”

Section: Discussionsupporting

confidence: 87%

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

et al. 2017

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Expression of the Ret receptor tyrosine kinase is a defining feature of enteric neurons. Its importance is underscored by the effects of its mutation in Hirschsprung disease, leading to absence of gut innervation and severe gastrointestinal symptoms. We report a new and physiologically significant site of Ret expression in the intestine: the intestinal epithelium. Experiments in Drosophila indicate that Ret is expressed both by enteric neurons and adult intestinal epithelial progenitors, which require Ret to sustain their proliferation. Mechanistically, Ret is engaged in a positive feedback loop with Wnt/Wingless signalling, modulated by Src and Fak kinases. We find that Ret is also expressed by the developing intestinal epithelium of mice, where its expression is maintained into the adult stage in a subset of enteroendocrine/enterochromaffin cells. Mouse organoid experiments point to an intrinsic role for Ret in promoting epithelial maturation and regulating Wnt signalling. Our findings reveal evolutionary conservation of the positive Ret/Wnt signalling feedback in both developmental and homeostatic contexts. They also suggest an epithelial contribution to Ret loss‐of‐function disorders such as Hirschsprung disease.

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Section: Discussionsupporting

confidence: 87%

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

et al. 2017

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“…Importantly, a number of small-molecule FAK tyrosine kinase inhibitors are currently undergoing preclinical and clinical testing. In particular, PF-00562271, VS-4718 and VS-6063 demonstrated promising clinical activity in patients with selected solid cancers, emphasizing their potential utility for sarcoma treatment (45,46).…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteomic Profiling Reveals ALK and MET as Novel Actionable Targets across Synovial Sarcoma Subtypes

et al. 2017

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Despite intensive multimodal treatment of sarcomas, a heterogeneous group of malignant tumors arising from connective tissue, survival remains poor. Candidate-based targeted treatments have demonstrated limited clinical success, urging an unbiased and comprehensive analysis of oncogenic signaling networks to reveal therapeutic targets and personalized treatment strategies. Here we applied mass spectrometry-based phosphoproteomic profiling to the largest and most heterogeneous set of sarcoma cell lines characterized to date and identified novel tyrosine phosphorylation patterns, enhanced tyrosine kinases in specific subtypes, and potential driver kinases. ALK was identified as a novel driver in the Aska-SS synovial sarcoma (SS) cell line via expression of an ALK variant with a large extracellular domain deletion (ALK D2-17 ). Functional ALK dependency was confirmed in vitro and in vivo with selective inhibitors. Importantly, ALK immunopositivity was detected in 6 of 43 (14%) of SS patient specimens, one of which exhibited an ALK rearrangement. High PDGFRa phosphorylation also characterized SS cell lines, which was accompanied by enhanced MET activation in Yamato-SS cells. Although Yamato-SS cells were sensitive to crizotinib (ALK/MET-inhibitor) but not pazopanib (VEGFR/PDGFR-inhibitor) monotherapy in vitro, synergistic effects were observed upon drug combination. In vivo, both drugs were individually effective, with pazopanib efficacy likely attributable to reduced angiogenesis. MET or PDGFRa expression was detected in 58% and 84% of SS patients, respectively, with coexpression in 56%. Consequently, our integrated approach has led to the identification of ALK and MET as promising therapeutic targets in SS.

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“…FAK activity is under complex control involving numerous elements and/or processes (Tomakidi et al 2014, Lee et al 2015. The SHB/FAK relationship is described above and this interaction will have implications for several downstream signaling systems, such as the Akt, ERK and Rac1 pathways as observed in b cells, endothelial cells and hematopoietic stem cells , Gustafsson et al 2013, Alenkvist et al 2014.…”

Section: Shb and The Fakmentioning

confidence: 96%

The role of the Src Homology-2 domain containing protein B (SHB) in β cells

Welsh

Jamalpour

Zang

et al. 2015

Journal of Molecular Endocrinology

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This review will describe the SH2-domain signaling protein Src Homology-2 domain containing protein B (SHB) and its role in various physiological processes relating in particular to glucose homeostasis and b cell function. SHB operates downstream of several tyrosine kinase receptors and assembles signaling complexes in response to receptor activation by interacting with other signaling proteins via its other domains (proline-rich, phosphotyrosine-binding and tyrosine-phosphorylation sites). The subsequent responses are context-dependent. Absence of Shb in mice has been found to exert effects on hematopoiesis, angiogenesis and glucose metabolism. Specifically, first-phase insulin secretion in response to glucose was impaired and this effect was related to altered characteristics of focal adhesion kinase activation modulating signaling through Akt, ERK, b catenin and cAMP. It is believed that SHB plays a role in integrating adaptive responses to various stimuli by simultaneously modulating cellular responses in different cell-types, thus playing a role in maintaining physiological homeostasis.

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FAK signaling in human cancer as a target for therapeutics

Cited by 350 publications

References 259 publications

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

Ret receptor tyrosine kinase sustains proliferation and tissue maturation in intestinal epithelia

Phosphoproteomic Profiling Reveals ALK and MET as Novel Actionable Targets across Synovial Sarcoma Subtypes

The role of the Src Homology-2 domain containing protein B (SHB) in β cells

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