title: Differential outcome of MEK1/2 inhibitor-platinum combinations in platinum-sensitive and -resistant ovarian carcinoma cells.
abstract: Deregulated pro-survival signalling plays a role in ovarian carcinoma drug resistance. Here, we show that cisplatin or oxaliplatin in combination with the MEK1/2 inhibitor CI-1040 resulted in a synergistic effect associated with enhanced apoptotic response in platinum-sensitive cells. The drug combinations were additive in platinum-resistant cells exhibiting increased phospho-ERK1/2, down-regulation of apoptosis-related factors (BAX, PUMA, FOXO1) and of phosphatases inhibiting ERK1/2 (DUSP5, DUSP6). Consistently, FOXO1 knockdown in sensitive cells reduced the efficacy of the combination treatment. Pharmacological targeting of ERK1/2 pathway increases cell sensitivity to platinum compounds by interfering with multiple events, ultimately favouring apoptosis induction in selected molecular backgrounds.
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, 20133 Milano, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Cossa
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, 20133 Milano, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Lanzi
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, 20133 Milano, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cassinelli
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, 20133 Milano, Italy.
authors.forename: Nives
authors.initials: N
authors.lastname: Carenini
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, 20133 Milano, Italy.
authors.forename: Noemi
authors.initials: N
authors.lastname: Arrighetti
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, 20133 Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Gatti
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, 20133 Milano, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Corna
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, 20133 Milano, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, 20133 Milano, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Amadeo 42, 20133 Milano, Italy. Electronic address: paola.perego@istitutotumori.mi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Perego
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D020287:In Situ Nick-End Labeling; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D009944:Organoplatinum Compounds; D020930:MAP Kinase Kinase Kinases
keywords: Drug resistance; FOXO1; MEK inhibitors; Ovarian carcinoma; Platinum compounds