Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Feb 10, 2016; 7(1): 106-113
Published online Feb 10, 2016. doi: 10.5306/wjco.v7.i1.106
Role of copper transporters in platinum resistance
Deepak Kilari, Elizabeth Guancial, Eric S Kim
Deepak Kilari, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, United States
Elizabeth Guancial, Eric S Kim, Departments of Medicine, University of Rochester Medical Center, Rochester, NY 14642, United States
Author contributions: All the authors contributed equally in writing the manuscript.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Eric S Kim, MD, Department of Medicine, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642, United States.
Telephone: +1-585-2734150 Fax: +1-585-2731042
Received: May 29, 2015
Peer-review started: May 31, 2015
First decision: August 4, 2015
Revised: October 20, 2015
Accepted: November 23, 2015
Article in press: November 25, 2015
Published online: February 10, 2016

Platinum (Pt)-based antitumor agents are effective in the treatment of many solid malignancies. However, their efficacy is limited by toxicity and drug resistance. Reduced intracellular Pt accumulation has been consistently shown to correlate with resistance in tumors. Proteins involved in copper homeostasis have been identified as Pt transporters. In particular, copper transporter receptor 1 (CTR1), the major copper influx transporter, has been shown to play a significant role in Pt resistance. Clinical studies demonstrated that expression of CTR1 correlated with intratumoral Pt concentration and outcomes following Pt-based therapy. Other CTRs such as CTR2, ATP7A and ATP7B, may also play a role in Pt resistance. Recent clinical studies attempting to modulate CTR1 to overcome Pt resistance may provide novel strategies. This review discusses the role of CTR1 as a potential predictive biomarker of Pt sensitivity and a therapeutic target for overcoming Pt resistance.

Keywords: Resistance, Cisplatin, Copper transporter receptor 1, Copper transporter, Copper transporter receptor 2, ATP7A, ATP7B

Core tip: Platinum (Pt)-based chemotherapy is the backbone of treatment for various solid malignancies in both curative and palliative settings. However, the efficacy of Pt is limited by toxicity and inevitable resistance. Hence, it is important to understand the mechanisms of Pt resistance to not only identify treatment non-responders, but more importantly to help develop strategies to overcome resistance and improve efficacy. We herein discuss our current understanding of the mechanisms of Pt resistance, with a particular emphasis on the role of copper transporter receptor 1 in Pt resistance.