title: Everolimus and pancreatic neuroendocrine tumors (PNETs): Activity, resistance and how to overcome it.
abstract: Neuroendocrine tumors (NET) are rare malignancies, with the most common site of origin being from the gastrointestinal tract, particularly the pancreas, small bowel and appendix. Pancreatic neuroendocrine tumors (PNETs) can be functional, hormone secreting tumors, and can have distinctive symptoms leading to the diagnosis. In contrast nonfunctional tumors, the majority of PNETs, usually present later either incidentally or due to tumor bulk symptoms. Currently Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), is the most promising drug for patients with unresectable, metastatic disease, in progressive well-differentiated PNETs and many studies are ongoing to demonstrate its effects on the other neuroendocrine histotipes. Food and Drug Administration (FDA) and European Medicines Agency (EMA) registered Everolimus in advanced/metastatic breast cancer, in advanced/metastatic renal cell carcinoma and in well/moderately differentiated pancreatic neuroendocrine tumors. Nevertheless only a subset of patients respond to the therapy due to the development of drug resistance. Thus the powerful Everolimus antitumor activity have prompted extensive efforts to overcome drug resistance and to maximize clinical benefit. In this review we aim to summarize current knowledge on mechanisms of Everolimus and other mTOR inhibitors molecules resistance with the intent to overcome it.
authors.affiliation: Pharmacy Unit, Istituto Nazionale Tumori, IRCCS - Fondazione G. Pascale, Naples, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Capozzi
authors.affiliation: Molecular Immunology and Immuneregulation Section, Functional Genomic Unit, Istituto Nazionale Tumori, IRCCS - Fondazione G. Pascale, Naples, Italy.
authors.forename: Ieranò
authors.initials: I
authors.lastname: Caterina
authors.affiliation: Department of Abdominal Oncology, Division of Medical Oncology, NCI "Fondazione G. Pascale", Naples, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: De Divitiis
authors.affiliation: Department of Clinical Medicine and Surgery, University Federico II of Naples, Naples, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: von Arx
authors.affiliation: Pharmacy Unit, Istituto Nazionale Tumori, IRCCS - Fondazione G. Pascale, Naples, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: Maiolino
authors.affiliation: Department of Diagnostic Pathology and Laboratory, Istituto Nazionale Tumori, IRCCS - Fondazione G. Pascale, Naples, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Tatangelo
authors.affiliation: Department of Diagnostic Pathology and Laboratory, Istituto Nazionale Tumori, IRCCS - Fondazione G. Pascale, Naples, Italy.
authors.forename: Ernesta
authors.initials: E
authors.lastname: Cavalcanti
authors.affiliation: Endoscopy Unit, Istituto Nazionale Tumori, IRCCS - Fondazione G. Pascale, Naples, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Di Girolamo
authors.affiliation: Department of Abdominal Oncology, Division of Medical Oncology, NCI "Fondazione G. Pascale", Naples, Italy.
authors.forename: Rosario Vincenzo
authors.initials: RV
authors.lastname: Iaffaioli
authors.affiliation: Molecular Immunology and Immuneregulation Section, Functional Genomic Unit, Istituto Nazionale Tumori, IRCCS - Fondazione G. Pascale, Naples, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Scala
authors.affiliation: Department of Abdominal Oncology, Division of Medical Oncology, NCI "Fondazione G. Pascale", Naples, Italy. Electronic address: s.tafuto@istitutotumori.na.it.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Tafuto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell; D019743:Chemokines, CXC / Q000502:physiology; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D000068338:Everolimus / Q000627:therapeutic use*; D006801:Humans; D018358:Neuroendocrine Tumors / Q000175:diagnosis; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D019707:Receptors, Chemokine / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D014481:United States
chemical_list: D000970:Antineoplastic Agents; D019743:Chemokines, CXC; D019707:Receptors, Chemokine; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Chemokine; Drug resistance; Everolimus; Pancreatic neuroendocrine tumor; m-TOR pathway