Chapter 2 - Drug transporters in the development of multidrug resistance in colorectal cancer

Abstract

Drug resistance is the major reason for treatment failure in colorectal cancer (CRC). Resistance can be intrinsic (primary resistance) or acquired (secondary resistance). Numerous mechanisms have been identified which contribute to drug resistance, including alterations in drug metabolism, mutations of drug targets, inactivation of apoptotic pathways, enhanced DNA damage repair, cancer stem cells, intra-tumor heterogeneity, and the Warburg effect. However, the most common and earliest resistance mechanism is widely believed to be the increase in drug efflux mediated by the ATP-binding cassette (ABC) transporters. Conventional cytotoxic anticancer drugs and the targeted chemotherapeutic drugs commonly used for treating CRC are substrates of the ABC transporters, therefore their anticancer efficacies are adversely affected by the transporter overexpression in drug-resistant cancer cells. Although limited reports are available about the use of transporter inhibitors to overcome drug resistance in CRC, it is important to acknowledge the significance of drug resistance in solid tumors and the well-known resistance-reversing agents identified in other tumor types. In the past, clinical trials investigating the combination of ABC transporter inhibitors and chemotherapeutic drugs for resistance reversal were conducted without the selection of patients whose tumors had high expression of ABC transporters. In the era of personalized medicine, it is possible to identify patients whose tumors overexpress ABC transporter(s). Anticancer drugs that are not transporter substrates should be chosen for these patients. Transporter inhibitors may also be included in chemotherapeutic regimens to improve the clinical outcome.