RET, a targetable driver of pancreatic adenocarcinoma

Amit, Moran; Na’ara, Shorook; Fridman, Eran; Vladovski, Euvgeni; Wasserman, Tanya; Milman, Neta; Gil, Ziv

doi:10.1002/ijc.32040

Cited by 12 publications

(4 citation statements)

References 48 publications

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“…RET is altered and potentially actionable in other solid tumor types, albeit at low frequencies. RET alterations occur in ~1.9% of pancreatic cancers ( 41 ) whereas wild-type RET, co-receptor GFRα1, and GDNF are overexpressed in 50-70% of pancreatic cancer cases ( 194 , 195 ). Additionally, Ceyhan and colleagues demonstrated that RET activation by another GFL, Artemin, can promote invasion and migration of pancreatic cancer cells ( 196 ).…”

Section: Aberrant Ret Signaling In Tumorigenesismentioning

confidence: 99%

RET signaling pathway and RET inhibitors in human cancer

Regua

Najjar

2022

Front. Oncol.

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Rearranged during transfection (RET) receptor tyrosine kinase was first identified over thirty years ago as a novel transforming gene. Since its discovery and subsequent pathway characterization, RET alterations have been identified in numerous cancer types and are most prevalent in thyroid carcinomas and non-small cell lung cancer (NSCLC). In other tumor types such as breast cancer and salivary gland carcinomas, RET alterations can be found at lower frequencies. Aberrant RET activity is associated with poor prognosis of thyroid and lung carcinoma patients, and is strongly correlated with increased risk of distant metastases. RET aberrations encompass a variety of genomic or proteomic alterations, most of which confer constitutive activation of RET. Activating RET alterations, such as point mutations or gene fusions, enhance activity of signaling pathways downstream of RET, namely PI3K/AKT, RAS/RAF, MAPK, and PLCγ pathways, to promote cell proliferation, growth, and survival. Given the important role that mutant RET plays in metastatic cancers, significant efforts have been made in developing inhibitors against RET kinase activity. These efforts have led to FDA approval of Selpercatinib and Pralsetinib for NSCLC, as well as, additional selective RET inhibitors in preclinical and clinical testing. This review covers the current biological understanding of RET signaling, the impact of RET hyperactivity on tumor progression in multiple tumor types, and RET inhibitors with promising preclinical and clinical efficacy.

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Section: Aberrant Ret Signaling In Tumorigenesismentioning

confidence: 99%

RET signaling pathway and RET inhibitors in human cancer

Regua

Najjar

2022

Front. Oncol.

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“…RET activation in cancers through RET fusions or mutations. ,,− CML, chronic myeloid leukemia; NSCLC, non-small cell lung cancer; PTC, papillary thyroid cancer; MTC, medullary thyroid cancer.…”

Section: Ret Implications In Cancermentioning

confidence: 99%

Targeting Rearranged during Transfection in Cancer: A Perspective on Small-Molecule Inhibitors and Their Clinical Development

et al. 2021

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Rearranged during transfection (RET) is a receptor tyrosine kinase essential for the normal development and maturation of a diverse range of tissues. Aberrant RET signaling in cancers, due to RET mutations, gene fusions, and overexpression, results in the activation of downstream pathways promoting survival, growth, and metastasis. Pharmacological manipulation of RET is effective in treating RET-driven cancers, and efforts toward developing RET-specific therapies have increased over the last 5 years. In 2020, RET-selective inhibitors pralsetinib and selpercatinib achieved clinical approval, which marked the first approvals for kinase inhibitors specifically developed to target the RET oncoprotein. This Perspective discusses current development and clinical applications for RET precision medicine by providing an overview of the incremental improvement of kinase inhibitors for use in RET-driven malignancies.

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“…Nerve growth factor (NGF) has been considered the most potent pain inducer across multiple cancer models and currently holds the most promise for management of pain associated with cancer initiation and progression. Inhibition of NGF binding to the receptor TrkA in preclinical models strongly reduced mechanical, thermal and spontaneous facets of cancer-induced bone pain ( Halvorson et al, 2005b ; Jimenez-Andrade et al, 2011 ; Buehlmann et al, 2019 ), pancreatic cancer pain ( Stopczynski et al, 2014 ; Amit et al, 2019 ), and oral cancer pain ( Ye et al, 2011 ). A phase II clinical trial using anti-NGF antibody, fulranumab, as adjunctive therapy for cancer-related pain found no significant effect on pain intensity via visual analog scale; however, significant improvement on the Brief Pain Inventory subscales suggested improved quality of life ( Slatkin et al, 2019 ).…”

Section: Animal Models Of Cancer-related Painmentioning

confidence: 99%

Animal Models of Cancer-Related Pain: Current Perspectives in Translation

2020

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The incidence of pain in cancer patients during diagnosis and treatment is exceedingly high. Although advances in cancer detection and therapy have improved patient prognosis, cancer and its treatment-associated pain have gained clinical prominence. The biological mechanisms involved in cancer-related pain are multifactorial; different processes for pain may be responsible depending on the type and anatomic location of cancer. Animal models of cancer-related pain have provided mechanistic insights into the development and process of pain under a dynamic molecular environment. However, while cancer-evoked nociceptive responses in animals reflect some of the patients’ symptoms, the current models have failed to address the complexity of interactions within the natural disease state. Although there has been a recent convergence of the investigation of carcinogenesis and pain neurobiology, identification of new targets for novel therapies to treat cancer-related pain requires standardization of methodologies within the cancer pain field as well as across disciplines. Limited success of translation from preclinical studies to the clinic may be due to our poor understanding of the crosstalk between cancer cells and their microenvironment (e.g., sensory neurons, infiltrating immune cells, stromal cells etc.). This relatively new line of inquiry also highlights the broader limitations in translatability and interpretation of basic cancer pain research. The goal of this review is to summarize recent findings in cancer pain based on preclinical animal models, discuss the translational benefit of these discoveries, and propose considerations for future translational models of cancer pain.

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RET, a targetable driver of pancreatic adenocarcinoma

Cited by 12 publications

References 48 publications

RET signaling pathway and RET inhibitors in human cancer

RET signaling pathway and RET inhibitors in human cancer

Targeting Rearranged during Transfection in Cancer: A Perspective on Small-Molecule Inhibitors and Their Clinical Development

Animal Models of Cancer-Related Pain: Current Perspectives in Translation

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