Medullary thyroid cancer: targeting the RET kinase pathway with sorafenib/tipifarnib

Hong, David S.; Ye, Lei; Gagel, Robert F.; Chintala, Lakshmi; Naggar, Adel K. El; Wright, John J.; Kurzrock, Razelle

doi:10.1158/1535-7163.mct-07-2422

Cited by 46 publications

(36 citation statements)

References 25 publications

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“…The antiproliferative activity of sorafenib varies widely depending on the oncogenic signaling pathways driving proliferation. For tumor cell lines with a single activating oncogenic tyrosine kinase mutation [such as MV4-11 and EOL-1 leukemic cell lines that contain a Flt-3 gene, mutant T670I cKIT that renders patients with gastrointestinal stromal tumor refractory to imatinib (29,30), or oncogenic RET variants (15,31) in metastatic thyroid cancer; ref. 32], the antiproliferative activity of sorafenib is in the low nanomolar concentration range (14,33).…”

Section: Targets For Sorafenibmentioning

confidence: 99%

Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling

Wilhelm

Adnane

Newell

et al. 2008

Molecular Cancer Therapeutics

1,267

861

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Although patients with advanced refractory solid tumors have poor prognosis, the clinical development of targeted protein kinase inhibitors offers hope for the future treatment of many cancers. In vivo and in vitro studies have shown that the oral multikinase inhibitor, sorafenib, inhibits tumor growth and disrupts tumor microvasculature through antiproliferative, antiangiogenic, and/or proapoptotic effects. Sorafenib has shown antitumor activity in phase II/III trials involving patients with advanced renal cell carcinoma and hepatocellular carcinoma. The multiple molecular targets of sorafenib (the serine/threonine kinase Raf and receptor tyrosine kinases) may explain its broad preclinical and clinical activity. This review highlights the antitumor activity of sorafenib across a variety of tumor types, including renal cell, hepatocellular, breast, and colorectal carcinomas in the preclinical setting. In particular, preclinical evidence that supports the different mechanisms of action of sorafenib is discussed. [Mol Cancer Ther 2008;7(10):3129 -40]

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Section: Targets For Sorafenibmentioning

confidence: 99%

Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling

Wilhelm

Adnane

Newell

et al. 2008

Molecular Cancer Therapeutics

1,267

861

View full text Add to dashboard Cite

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“…Although initially developed as an approach to target RAS in cancer, FTI have later been recognized as acting by additional and more complex mechanisms, involving RhoB, centromere-binding proteins and probably other farnesylated proteins. Hong et al (2008) reported on a patient with sporadic MTC with metastatic disease, who was treated with a combination of sorafenib (RET and RAF kinase and vascular endothelial growth factor receptor inhibitor) and tipifarnib (inhibitor of RAS farnesylation), which resulted in a marked clinical response. In a phase I study, it was shown that combining the multikinase inhibitor sorafenib with the FTI tipifarnib resulted in significant activity, particularly in patients with RET mutations (Hong et al 2009).…”

Section: Ras Mutations As a Therapeutic Target In Mtcmentioning

confidence: 99%

RAS proto-oncogene in medullary thyroid carcinoma

Moura¹,

Cavaco²,

Leite³

2015

Endocrine-Related Cancer

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Medullary thyroid carcinoma (MTC) is a rare malignancy originating from the calcitoninsecreting parafollicular thyroid C cells. Approximately 75% of cases are sporadic. Rearranged during transfection (RET) proto-oncogene plays a crucial role in MTC development. Besides RET, other oncogenes commonly involved in the pathogenesis of human cancers have also been investigated in MTC. The family of human RAS genes includes the highly homologous HRAS, KRAS, and NRAS genes that encode three distinct proteins. Activating mutations in specific hotspots of the RAS genes are found in about 30% of all human cancers. In thyroid neoplasias, RAS gene point mutations, mainly in NRAS, are detected in benign and malignant tumors arising from the follicular epithelium. However, recent reports have also described RAS mutations in MTC, namely in HRAS and KRAS. Overall, the prevalence of RAS mutations in sporadic MTC varies between 0-43.3%, occurring usually in tumors with WT RET and rarely in those harboring a RET mutation, suggesting that activation of these proto-oncogenes represents alternative genetic events in sporadic MTC tumorigenesis. Thus, the assessment of RAS mutation status can be useful to define therapeutic strategies in RET WT MTC. MTC patients with RAS mutations have an intermediate risk for aggressive cancer, between those with RET mutations in exons 15 and 16, which are associated with the worst prognosis, and cases with other RET mutations, which have the most indolent course of the disease. Recent results from exome sequencing indicate that, besides mutations in RET, HRAS, and KRAS, no other recurrent driver mutations are present in MTC.

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“…However, none of these inhibitors are FDA approved on the basis of targeting RET aberrations. Meanwhile, there are a series of reports suggesting that matched therapies against RET aberrations can yield significant responses (8,15,(21)(22)(23)(24)(25)(26)(27). Further clinical trials with a focus on RET-aberrant advanced cancer are being conducted to determine impact on outcome (Supplementary Table S1).…”

Section: Introductionmentioning

confidence: 99%

RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients

Kato

Subbiah

Marchlik³

et al. 2017

Clinical Cancer Research

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229

157

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Purpose: Aberrations in genetic sequences encoding the tyrosine kinase receptor RET lead to oncogenic signaling that is targetable with anti-RET multikinase inhibitors. Understanding the comprehensive genomic landscape of RET aberrations across multiple cancers may facilitate clinical trial development targeting RET.Experimental Design: We interrogated the molecular portfolio of 4,871 patients with diverse malignancies for the presence of RET aberrations using Clinical Laboratory Improvement Amendments-certified targeted next-generation sequencing of 182 or 236 gene panels.Results

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Medullary thyroid cancer: targeting the RET kinase pathway with sorafenib/tipifarnib

Cited by 46 publications

References 25 publications

Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling

Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling

RAS proto-oncogene in medullary thyroid carcinoma

RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients

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