Journal
ENDOCRINE-RELATED CANCER
Volume 26, Issue 3, Pages R109-R130Publisher
BIOSCIENTIFICA LTD
DOI: 10.1530/ERC-18-0420
Keywords
rapalog; sunitinib; resistance; neuroendocrine tumors; targeted treatment
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Funding
- Flemish Agency of Scientifc Research (FWO) [G.0327.13N]
- Kom op tegen Kanker (Stand up to Cancer, the Flemish Cancer Society)
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The mammalian target of rapamycin (mTOR) is part of the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mTOR signaling. The PI3K/Akt/mTOR pathway has a pivotal role in the oncogenesis of neuroendocrine tumors (NETs). In addition, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) drive angiogenesis in NETs and therefore contributes to neuroendocrine tumor development. Hence, mTOR and angiogenesis inhibitors have been developed. Everolimus, a first-generation mTOR inhibitor, has shown significant survival benefit in advanced gastroenteropancreatic NETs. Sunitinib, a pan-tyrosine kinase inhibitor that targets the VEGF receptor, has proven to increase progression-free survival in advanced pancreatic NETs. Nevertheless, primary and acquired resistance to rapalogs and sunitinib has limited the clinical benefit for NET patients. Despite the identification of multiple molecular mechanisms of resistance, no predictive biomarker has made it to the clinic. This review is focused on the mTOR signaling and angiogenesis in NET, the molecular mechanisms of primary and acquired resistance to everolimus and sunitinib and how to overcome this resistance by alternative drug compounds.
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