title: Enzastaurin inhibits tumours sensitive and resistant to anti-EGFR drugs.
abstract: We investigated the antitumour effect and ability to overcome the resistance to anti-EGFR drugs of enzastaurin, an inhibitor of VEGFR-dependent PKCbeta signalling. Enzastaurin was evaluated alone and in combination with the EGFR inhibitor gefitinib, on growth and signalling protein expression in human cancer cells sensitive and resistant to anti-EGFR drugs, both in vitro and in nude mice. We demonstrated the marked inhibitory activity of enzastaurin against GEO colon and PC3 prostate cancer cells and their gefitinib-resistant counterparts GEO-GR and PC3-GR, accompanied by inhibition of pAkt and its effector pp70S6K, pGSK3beta and VEGF expression and secretion. Moreover, enzastaurin showed a cooperative effect with gefitinib in parental and in gefitinib-resistant cells. Remarkably, these results were confirmed in vivo, where enzastaurin showed antitumour activity and cooperativity with gefitinib in mice grafted with GEO and GEO-GR tumours, incrementing their median survival and inhibiting the aforesaid protein expression and secretion in tumour specimens. In conclusion, enzastaurin by interfering with signalling proteins implicated in EGFR drug resistance markedly cooperates with gefitinib in sensitive and gefitinib-resistant tumours, thus overcoming and reverting such resistance and providing a rational basis for its development in patients resistant to anti-EGFR drugs.
authors.affiliation: Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università di Napoli Federico II, Napoli, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Gelardi
authors.forename: R
authors.initials: R
authors.lastname: Caputo
authors.forename: V
authors.initials: V
authors.lastname: Damiano
authors.forename: G
authors.initials: G
authors.lastname: Daniele
authors.forename: S
authors.initials: S
authors.lastname: Pepe
authors.forename: F
authors.initials: F
authors.lastname: Ciardiello
authors.forename: M
authors.initials: M
authors.lastname: Lahn
authors.forename: R
authors.initials: R
authors.lastname: Bianco
authors.forename: G
authors.initials: G
authors.lastname: Tortora
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D004354:Drug Screening Assays, Antitumor; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D007211:Indoles; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D000077156:Gefitinib; C504878:enzastaurin