Targeting the receptor tyrosine kinase RET in combination with aromatase inhibitors in ER positive breast cancer xenografts

Andreucci, Elena; Francica, Paola; Fearns, Antony; Martin, Lesley-Ann; Chiarugi, Paola; Isacke, Clare M.; Morandi, Andrea

doi:10.18632/oncotarget.11826

Cited by 28 publications

(28 citation statements)

References 28 publications

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“…GDNF is also able to increase VEGF-VEGFR interaction enhancing the migration of colon cancer cells [96]. In case of glioma or breast cancers, the GDNF-Ret signaling pathway can be blocked by GAS1 (growth arrest-specific 1) or by some Ret kinase inhibitors leading to the impairment of tumor growth [97,98]. GFLs are also linked with hepatocellular carcinoma (HCC), as high expression of GFRα3 or phosphorylation of Ret in HCC tissues and an increase of ARTN in the serum correlate with poor prognosis in HCC patients.…”

Section: In Cancersmentioning

confidence: 99%

Revisiting the Role of Neurotrophic Factors in Inflammation

Morel

Domingues

Zimmer

et al. 2020

Cells

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The neurotrophic factors are well known for their implication in the growth and the survival of the central, sensory, enteric and parasympathetic nervous systems. Due to these properties, neurturin (NRTN) and Glial cell-derived neurotrophic factor (GDNF), which belong to the GDNF family ligands (GFLs), have been assessed in clinical trials as a treatment for neurodegenerative diseases like Parkinson’s disease. In addition, studies in favor of a functional role for GFLs outside the nervous system are accumulating. Thus, GFLs are present in several peripheral tissues, including digestive, respiratory, hematopoietic and urogenital systems, heart, blood, muscles and skin. More precisely, recent data have highlighted that different types of immune and epithelial cells (macrophages, T cells, such as, for example, mucosal-associated invariant T (MAIT) cells, innate lymphoid cells (ILC) 3, dendritic cells, mast cells, monocytes, bronchial epithelial cells, keratinocytes) have the capacity to release GFLs and express their receptors, leading to the participation in the repair of epithelial barrier damage after inflammation. Some of these mechanisms pass on to ILCs to produce cytokines (such as IL-22) that can impact gut microbiota. In addition, there are indications that NRTN could be used in the treatment of inflammatory airway diseases and it prevents the development of hyperglycemia in the diabetic rat model. On the other hand, it is suspected that the dysregulation of GFLs produces oncogenic effects. This review proposes the discussion of the biological understanding and the potential new opportunities of the GFLs, in the perspective of developing new treatments within a broad range of human diseases.

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Section: In Cancersmentioning

confidence: 99%

Revisiting the Role of Neurotrophic Factors in Inflammation

Morel

Domingues

Zimmer

et al. 2020

Cells

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“…Andreucci et al [109] (2016) demonstrated that a major cause of AI resistance is ligand-independent ER activation induced by activation of growth factor receptor(s) through PI3K/AKT/mTOR or MAPK [64,[118][119][120][121] . Thus, BC cells are able to escape the growth-control effect of endocrine drugs by increasing estrogen-independent ER activity [ Figure 3].…”

Section: Mechanisms Of Drug Resistance In Bcmentioning

confidence: 99%

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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“…Notably, RET expression appeared to increase in tumors with high residual proliferation and decreased in tumors gaining greater benefit from AI therapy. As noted above, RET has been linked with resistance to therapy and its potential as a therapeutic target has been suggested (37,38).…”

Section: Discussionmentioning

confidence: 99%

Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors

Leal

Haynes

Schuster

et al. 2019

Clinical Cancer Research

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Purpose: To investigate the presence of ESR1 mutations in primary estrogen-receptor-positive (ER þ) breast cancer treated with extended (>4 weeks) neoadjuvant (presurgical) aromatase inhibitor (NAI) therapy and to identify patients who may gain less benefit from aromatase inhibition (AI) alone based upon on-treatment changes in gene expression. Experimental Design: We evaluated ER, progesterone receptor, and Ki67 by immunostaining, ESR1 mutations by droplet-digital PCR and expression of over 800 key breast cancer genes in paired pre-and post-NAI tumor samples from 87 ER þ breast cancer patients. Results: Cell proliferation and estrogen-regulated genes (ERG) remained suppressed in most tumors indicative of persistent response to NAI. Enrichment of ESR1 mutations was found in five tumors and predominantly in patients receiving therapy for >6 months. ESR1-mutant tumors showed increased expression of ESR1 transcript and limited suppression of ERGs and proliferation-associated genes in response to NAI. ESR1 wild-type tumors with high residual proliferation (Ki67r !10%; 15/87 tumors) showed lower ESR1/ER expression pre-and post-therapy and lower ERGs. Tumors with ESR1 mutations or Ki67r !10% showed less inhibition of estrogen response, cell cycle, and E2F-target genes. Conclusions: Ligand-independent ER signaling, as a result of ESR1 mutation or reduced ER dependence, identified after extended NAI therapy, can guide early selection of patients who would benefit from combination therapy.

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Targeting the receptor tyrosine kinase RET in combination with aromatase inhibitors in ER positive breast cancer xenografts

Cited by 28 publications

References 28 publications

Revisiting the Role of Neurotrophic Factors in Inflammation

Revisiting the Role of Neurotrophic Factors in Inflammation

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

Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors

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