Human ATP-Binding Cassette transporters ABCB1 and ABCG2 confer resistance to CUDC-101, a multi-acting inhibitor of histone deacetylase, epidermal growth factor receptor and human epidermal growth factor receptor 2.

Abstract

CUDC-101 is the first small-molecule inhibitor designed to simultaneously inhibit epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2) and histone deacetylase (HDAC) in cancer cells. Recently, in its first in human phase I study, CUDC-101 showed promising single agent activity against advanced solid tumors and favorable pharmacodynamic profile. However, the risk of developing drug resistance to CUDC-101 can still present a significant therapeutic challenge to clinicians in the future. One of the most common mechanisms of developing multidrug resistance (MDR) in cancer is associated with the overexpression of ATP-binding cassette (ABC) drug transporters ABCB1 and ABCG2. Together, they are able to reduce the efficacy and modify the pharmacological properties of anti-cancer agents, including many small molecule tyrosine kinase inhibitors (TKIs). Here, we have investigated the impact of ABCB1 and ABCG2 on the efficacy of CUDC-101 in human cancer cells. We revealed that although CUDC-101 has potent antiproliferative and proapoptotic activities against most cancer cell lines, the overexpression of ABCB1 or ABCG2 in cancer cells significantly reduced the activity of CUDC-101 against HDAC, EGFR and HER2, as well as its cytotoxicity and proapoptotic activity. Moreover, we showed that CUDC-101 modulated the function of both transporters without affecting the protein expression of either ABCB1 or ABCG2. More importantly, our study provides support for the rationale of combining CUDC-101 with modulators of ABC drug transporters to improve drug efficacy and overcome multidrug resistance associated with the overexpression of ABCB1 and ABCG2.

• Authors: Chung-Pu Wu, Sung-Han Hsiao, Ching-Ya Su, Shi-Yu Luo, Yan-Qing Li, Yang-Hui Huang, Chia-Hung Hsieh, Chiun-Wei Huang
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 92 Issue 4 Pg. 567-76 (Dec 15 2014) ISSN: 1873-2968 [Electronic] England
• PMID: 25450670 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide
• ABCB1 protein, human
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Neoplasm Proteins
• Quinazolines
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2

Topics

• ATP Binding Cassette Transporter, Subfamily B (physiology)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (physiology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• ErbB Receptors (antagonists & inhibitors)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Hydroxamic Acids (pharmacology)
• Neoplasm Proteins (physiology)
• Quinazolines (pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors)