Critical focus on mechanisms of resistance and toxicity of m-TOR inhibitors in pancreatic neuroendocrine tumors

Autor: Giuliana Restante, F. Di Costanzo, Nicola Fazio, M. Del Re, Giulia Meoni, Francesca Spada, Romano Danesi, Lorenzo Antonuzzo, Viola Barucca
Rok vydání: 2017
Předmět:
0301 basic medicine
Resistance
Drug resistance
Neuroendocrine tumors
Pharmacology
medicine.disease_cause
PI3K
Phosphatidylinositol 3-Kinases
03 medical and health sciences
0302 clinical medicine
Nuclear Medicine and Imaging
BEZ-235
mTOR
Pancreatic neuroendocrine tumors
Toxicity
Oncology
Radiology
Nuclear Medicine and Imaging
medicine
Animals
Humans
Radiology
Nuclear Medicine and imaging
Protein Kinase Inhibitors
Protein kinase B
PI3K/AKT/mTOR pathway
Everolimus
business.industry
TOR Serine-Threonine Kinases
General Medicine
medicine.disease
Pancreatic Neoplasms
Clinical trial
Neuroendocrine Tumors
030104 developmental biology
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Cancer research
Radiology
Carcinogenesis
business
Proto-Oncogene Proteins c-akt
Signal Transduction
medicine.drug
Zdroj: Cancer Treatment Reviews. 57:28-35
ISSN: 0305-7372
DOI: 10.1016/j.ctrv.2017.05.001
Popis: Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms representing less than 2% of all pancreatic malignancies. The PI3K-AKT-mTOR pathway is often deregulated in pNETs and seems to play a key role in tumorigenesis. Everolimus, an inhibitor of the mTOR pathway, has demonstrated efficacy in the treatment of pNETs. Nevertheless de novo or acquired drug resistance is responsible for disease progression and represents a major obstacle to overcome by clinicians. Blocking the PI3K/AKT/mTOR pathway may cover the supposed main mechanisms of resistance to everolimus. Therefore, BEZ-235, a potent oral dual PI3K/mTOR inhibitor was investigated in clinical trials. Globally more than 250 patients with different types of solid tumors were treated. Two studies were conducted in pNETs with BEZ-235 as single agent. The former was a phase 2 trial conducted in pNETs resistant to everolimus while the latter a randomized trial comparing everolimus and BEZ-235. Unfortunately, both the studies disappointed the expectations and were prematurely halted mainly due to severe toxicity. On this basis we reviewed m-TOR inhibitors in pNETs, focusing on their mechanisms of resistance and toxicity.
Databáze: OpenAIRE
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