Targeting Focal Adhesion Kinase and Resistance to mTOR Inhibition in Pancreatic Neuroendocrine Tumors

François, R; Maeng, Kyungah; Nawab, Akbar; Kaye, Frederic J.; Hochwald, Steven N.; Zajac-Kaye, Maria

doi:10.1093/jnci/djv123

Cited by 43 publications

(33 citation statements)

References 44 publications

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“…7). attractive (42). In a previous study, it was demonstrated that inactivation of FAK, coupled with inhibition of mTOR by everolimus, led to increased apoptosis of PNET cells by preventing feedback activation of AKT (42).…”

Section: Discussionmentioning

confidence: 99%

Pancreatic Neuroendocrine Tumors and EMT Behavior Are Driven by the CSC Marker DCLK1

Ikezono

Koga

Akiba

et al. 2017

Molecular Cancer Research

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Doublecortin-like kinase 1 (DCLK1), a marker for intestinal and pancreatic cancer stem cells, is highly expressed in neuroblastomas. This study was conducted to assess DCLK1 expression levels in pancreatic neuroendocrine tumor (PNET) tissues and to explore the roles of this molecule in clinical tissue from multiple PNET patients, cells (BON1, QGP1, and CM) and tumor xenografts. Immunohistochemically, all PNET tissues highly and diffusely expressed DCLK1 as a full-length isoform, identical to that detected in primary liver NETs. A DCLK1-overexpressing PNET cell line (QGP1-DCLK1) exhibited epithelial-mesenchymal transition (EMT)-related gene signatures, and robust upregulation of Slug (SNAI2), N-Cadherin (CDH2), and Vimentin (VIM) was validated by real-time PCR and immunoblotting. QGP1-DCLK1 cells had increased cell migration in a wound-healing assay and formed significantly larger xenograft tumors in nude mice. The factors involved in the formation of the fast-growing tumors included p-FAK (on Tyr925), p-ERK1/2, p-AKT, Paxillin, and Cyclin D1, which upon knockdown or pharmacologic inhibition of DCLK1 abolished the expression of these molecules. In conclusion, robust and ubiquitous expression of DCLK1 was first demonstrated here in human PNET tissue specimens and cells. DCLK1 characterized the PNET cell behavior, inducing p-FAK/SLUG-mediated EMT. These findings suggest the possibility of developing novel therapeutic strategies against PNETs by targeting DCLK1. Evidence here reveals that human PNETs diffusely and robustly express the cancer stem cell marker DCLK1, which drives SLUG-mediated EMT, and suggests that NETs share biological features for druggable targets with other tumors, including neuroblastoma that also highly expresses DCLK1. .

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Section: Discussionmentioning

confidence: 99%

Pancreatic Neuroendocrine Tumors and EMT Behavior Are Driven by the CSC Marker DCLK1

Ikezono

Koga

Akiba

et al. 2017

Molecular Cancer Research

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“…Specifically, the authors reported that inhibition of Src resulted in decreased FAK phosphorylation suggesting that a reduction of FAK activity may be a useful strategy to reduce fibronectin mediated effects on tumor cell migration and invasion 29. In addition to indirect targets of FAK, it may be possible to directly reduce FAK activity via use of a novel ATP competitive kinase inhibitor, PF-04554878, which was recently shown to promote apoptosis and reduce proliferation of pancreatic neuroendocrine tumor cells 37.…”

Section: Future Outlook: Potential Strategies For Targeting Fibronectinmentioning

confidence: 99%

Fibronectin: How Its Aberrant Expression in Tumors May Improve Therapeutic Targeting

Wang¹,

Hielscher²

2017

J. Cancer

151

134

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Fibronectin is a matrix glycoprotein which has not only been found to be over-expressed in several cancers, but has been shown to participate in several steps of tumorigenesis. The purpose of this review is to illustrate how aberrant fibronectin expression influences tumor growth, invasion, metastasis and therapy resistance. In particular, this review will focus on the interactions between cell receptor ligands and fibronectin and how this interaction influences downstream signaling events that aid tumor progression. This review will further discuss the possible implications of therapeutic drugs directed against fibronectin and/or cellular interactions with fibronectin and will additionally discuss novel approaches by which to limit intra- and extra-tumoral fibronectin expression and the cellular events which lead to aberrant fibronectin expression. It is anticipated that these studies will set a basis for future research that will not only aid understanding of fibronectin and its prognostic significance, but will further elucidate novel targets for therapeutics.

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“…Ongoing research is currently investigating whether specific RET mutations could predict the success of treatment with receptor kinase inhibitors (NCT01945762) in MTC. Another hypothesis that needs to be tested is that mutations in genes involved in mTOR signaling could be used as biomarkers of rapalogue response (155,156).development of future therapies: both combination therapy with FAK and mTOR inhibitors (157) as well as inhibition of B-catenin in MEN1 deficient pancreatic NETs (158). Immunotherapy is also an emerging branch in cancer treatment where the knowledge of tumor genetics and biology has proved to be important for prediction.…”

Section: Authors Perspectives and Future Implicationsmentioning

confidence: 99%

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

Crona

Skogseid

2016

European Journal of Endocrinology

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Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel-Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.

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Targeting Focal Adhesion Kinase and Resistance to mTOR Inhibition in Pancreatic Neuroendocrine Tumors

Cited by 43 publications

References 44 publications

Pancreatic Neuroendocrine Tumors and EMT Behavior Are Driven by the CSC Marker DCLK1

Pancreatic Neuroendocrine Tumors and EMT Behavior Are Driven by the CSC Marker DCLK1

Fibronectin: How Its Aberrant Expression in Tumors May Improve Therapeutic Targeting

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

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