GDNF and the RET Receptor in Cancer: New Insights and Therapeutic Potential

Mulligan, Lois M.

doi:10.3389/fphys.2018.01873

Cited by 83 publications

(103 citation statements)

References 167 publications

(243 reference statements)

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“…The involvement of RET in the pathogenesis of BC has been confirmed by several independent studies [51,60] . A subset of ER+ tumors showed an overexpression of RET and GFRα 1 [61][62][63] , which correlates with decreased metastasis-free survival [64,65] , thus confirming the importance of RET in the development of ER+ cancers and making it a promising target to avoid tamoxifen resistance and improve effects of hormone therapy in BC [60] .…”

Section: Introductionmentioning

confidence: 67%

RET in breast cancer: pathogenic implications and mechanisms of drug resistance

Nigro¹,

Rusmini²,

Ceccherini³

2019

CDR

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Initiation, progression, outcome and sensibility to therapies in breast cancer (BC), the most frequent cancer in women, are driven by somatic and germline mutations. Although the effectiveness of hormonal therapies is well-founded, it is prescribed for cancers which express steroid hormone receptors, such as estrogen receptor (ER). RET is a protooncogene encoding a transmembrane tyrosine kinase receptor that is activated by one of its four ligands (GDNF, neurturin, artemin or persephin) and one of its coreceptors (Gfrα1-4). Loss-of-function mutations in RET are responsible for Hirschsprung disease, while gain-of-function mutations for multiple endocrine neoplasia type 2. In addition, deregulation of its intracellular signaling, due to mutations, gene rearrangements, overexpression or transcriptional upregulation, can cause several neuroendocrine and epithelial tumors. In BC, amplification of receptor tyrosine kinases, such as ERBB2, EGFR, IGFR and FGFR1, and/or their upregulation contribute to cancer initiation and progression. RET can also have an important role in BC, but only in the subset of ER-positive (ER+) tumors, where it is found overexpressed. Targeting the RET pathway and shedding light on molecular basis of the resistance to hormone therapy may lead to new therapies in ER+ BC, improving treatment outcome and preventing tumor-related events. Thus, here, we review the state of the art of RET biology in BC and agents targeting RET tested in the clinical trials and discuss the specificity of the still available RET inhibitors and the molecular mechanisms underlying the BC resistance to endocrine therapy.

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Section: Introductionmentioning

confidence: 67%

RET in breast cancer: pathogenic implications and mechanisms of drug resistance

Nigro¹,

Rusmini²,

Ceccherini³

2019

CDR

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“…A lot of research has been conducted on mutated constitutively active forms of RET, which play a major role in thyroid cancer, pheochromocytoma, and parathyroid hyperplasia, as well as in the development of lung cancer in a subset of patients. In recent years, the reports regarding the role of wild-type RET activated by its cognate ligands in the progression of tumors originating from other tissues started to appear [ 102 , 103 ], but this field is much less studied, and final conclusions are yet to be made.…”

Section: Role Of Ret In Various Disease Statesmentioning

confidence: 99%

RET Receptor Tyrosine Kinase: Role in Neurodegeneration, Obesity, and Cancer

Mahato

Sidorova

2020

IJMS

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Rearranged during transfection (RET) is the tyrosine kinase receptor that under normal circumstances interacts with ligand at the cell surface and mediates various essential roles in a variety of cellular processes such as proliferation, differentiation, survival, migration, and metabolism. RET plays a pivotal role in the development of both peripheral and central nervous systems. RET is expressed from early stages of embryogenesis and remains expressed throughout all life stages. Mutations either activating or inhibiting RET result in several aggressive diseases, namely cancer and Hirschsprung disease. However, the physiological ligand-dependent activation of RET receptor is important for the survival and maintenance of several neuronal populations, appetite, and weight gain control, thus providing an opportunity for the development of disease-modifying therapeutics against neurodegeneration and obesity. In this review, we describe the structure of RET, its signaling, and its role in both normal conditions as well as in several disorders. We highlight the differences in the signaling and outcomes of constitutive and ligand-induced RET activation. Finally, we review the data on recently developed small molecular weight RET agonists and their potential for the treatment of various diseases.

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“…Among the genes correlating strongly with chemoattraction, several have established roles in metastasis; for example, glial cell line‐derived neurotrophic factor (GDNF) ( R = .951) is a soluble ligand that can activate motility and metastasis in cancer cells 19‐21 and BMP2 ( R = .942) also encodes for a secreted protein with a role in cancer 22,23 . Among the genes with negative correlation WNT10B ( R = −.849) encodes for a ligand with a well‐established role in metastasis 24,25 and AES ( R = −.875) has been described as an endogenous metastasis suppressor 26,27 .…”

Section: Resultsmentioning

confidence: 99%

A strategy for the identification of paracrine regulators of cancer cell migration

Chavez

Farmaki

Zhang

et al. 2020

Clin Exp Pharma Physio

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We hypothesized that the correlation of the whole transcriptome with quantifiable phenotypes may unveil genes contributing to the regulation of the corresponding response. We tested this hypothesis in cultured fibroblasts exposed to diverse pharmacological and biological agents, to identify genes influencing chemoattraction of breast cancer cells. Our analyses revealed several genes that correlated, either positively or negatively with cell migration, suggesting that they may operate as activators or inhibitors of this process. Survey of the scientific literature showed that genes exhibiting positive or negative association with cell migration had frequently been linked to cancer and metastasis before, while those with minimal association were not. The current methodology may formulate the basis for the development of novel strategies linking genes to quantifiable phenotypes.

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GDNF and the RET Receptor in Cancer: New Insights and Therapeutic Potential

Cited by 83 publications

References 167 publications

RET in breast cancer: pathogenic implications and mechanisms of drug resistance

RET in breast cancer: pathogenic implications and mechanisms of drug resistance

RET Receptor Tyrosine Kinase: Role in Neurodegeneration, Obesity, and Cancer

A strategy for the identification of paracrine regulators of cancer cell migration

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