title: Signalling pathways passing Src in pancreatic endocrine tumours: relevance for possible combined targeted therapies.
abstract: The most frequent molecular abnormalities in pancreatic endocrine tumours (PETs) are mutations of the MEN1 gene, deregulation of the PI3K/AKT/mTOR signalling pathway and overactivation of growth factors and their receptors, such as the VEGF. On this basis, everolimus (Afinitor®; Novartis) and sunitinib (Sutent®; Pfizer) have both been approved by the FDA for the treatment of progressive, unresectable, locally advanced or metastatic PETs. However, molecular or surrogate markers able to predict the response of PET patients to treatment with these drugs are not available, and cancer cells treated with targeted therapies might develop escape pathways that evoke pro-survival feedback responses. The existence of cross-talk between different molecular pathways in PETs has been poorly investigated. In the present review, we present data supporting an important role for Src family kinases (SFKs) in PETs, together with the recent observation of a novel role for SFK in modulating the mTOR pathway activity. Of note, while treatment with everolimus triggered the activation of a survival response dependent on PI3K/AKT signalling in vitro, the simultaneous inhibition of SFKs blocked the activation of this unwanted escape signal. These studies might set the ground for the investigation of combined treatment of PETs with SFK and mTOR inhibitors.
authors.affiliation: Digestive and Liver Disease Unit, II Medical School, University of Rome La Sapienza, Rome, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Capurso
authors.forename: Alessia
authors.initials: A
authors.lastname: Di Florio
authors.forename: Claudio
authors.initials: C
authors.lastname: Sette
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Delle Fave
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D004701:Endocrine Gland Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D019061:src-Family Kinases; D058570:TOR Serine-Threonine Kinases