Oncotarget

Research Papers:

PLK1 is a critical determinant of tumor cell sensitivity to CPT11 and its inhibition enhances the drug antitumor efficacy in squamous cell carcinoma models sensitive and resistant to camptothecins

Valentina Zuco, Michelandrea De Cesare, Nadia Zaffaroni, Cinzia Lanzi and Giuliana Cassinelli _

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Oncotarget. 2015; 6:8736-8749. https://doi.org/10.18632/oncotarget.3538

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Abstract

Valentina Zuco1, Michelandrea De Cesare1, Nadia Zaffaroni1, Cinzia Lanzi1,* and Giuliana Cassinelli1,*

1 Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

* These authors contributed equally to this work

Correspondence to:

Giuliana Cassinelli, email:

Keywords: CPT11, PLK1, BI2536, squamous cell carcinoma, combination treatment

Received: December 11, 2014 Accepted: February 10, 2015 Published: March 12, 2015

Abstract

Intrinsic and acquired tumor drug resistance limits the therapeutic efficacy of camptothecins (CPTs). Downregulation of the mitotic kinase PLK1 was found associated with apoptosis induced by SN38 (CPT11 active metabolite). We investigated the role of PLK1 in the cell response to CPTs in squamous cell carcinoma (SCC) and pediatric sarcoma cell lines and explored the therapeutic potential of the combination of CPT11 and the PLK1 inhibitor BI2536 in CPT-sensitive and -resistant tumor models. Gain- and loss-of-function experiments established a direct role for PLK1 in counteracting SN38 antiproliferative and pro-apoptotic effects. The ability to activate an efficient G2/M cell cycle checkpoint allowing PLK1 ubiquitination and degradation was found associated with SN38-induced apoptosis in SCC cells. However, the synergistic interaction between SN38 and BI2536 enhanced apoptosis in cell lines both sensitive and resistant to SN38-induced apoptotic cell death. A well-tolerated CPT11/BI2536 cotreatment resulted in improved antitumor effect against SCC xenografts in mice compared to single agent treatments. The increased apoptosis induction was reflected in a high rate of complete responses and cures in mice harboring SCC, including tumors with intrinsic or acquired resistance to CPTs. PLK1 inhibition represents a promising strategy to improve the antitumor efficacy of CPT11-based regimens.


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