Differential outcome of MEK1/2 inhibitor-platinum combinations in platinum-sensitive and -resistant ovarian carcinoma cells

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• 作者：Giacomo Cossa¹ ; Cinzia Lanzi ; Giuliana Cassinelli ; Nives Carenini ; Noemi Arrighetti ; Laura Gatti ; Elisabetta Corna ; Franco Zunino ; Nadia Zaffaroni ; Paola Perego ; ^{paola.perego@istitutotumori.mi.it" class="auth_mail}
• 关键词：MEK inhibitors ; FOXO1 ; Platinum compounds ; Ovarian carcinoma ; Drug resistance
• 刊名：Cancer Letters
• 出版年：1 June, 2014
• 年：2014
• 卷：347
• 期：2
• 页码：212-224
• 全文大小：2742 K

文摘

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.