Elsevier

Drug Resistance Updates

Volume 8, Issues 1–2, February–April 2005, Pages 15-26
Drug Resistance Updates

Tyrosine kinase inhibitor resistance in cancer: role of ABC multidrug transporters

https://doi.org/10.1016/j.drup.2005.02.002Get rights and content

Abstract

Recent antitumor drug research has seen the development of a large variety of tyrosine kinase inhibitors (TKIs) with increasing specificity and selectivity. These are highly promising agents for specific inhibition of malignant cell growth and metastasis. However, their therapeutic potential also depends on access to their intracellular targets, which may be significantly affected by certain ABC membrane transporters. It has been recently shown that several human multidrug transporter ABC proteins interact with specific TKIs, and the ABCG2 transporter has an especially high affinity for some of these kinase inhibitors. These results indicate that multidrug resistance protein modulation by TKIs may be an important factor in the treatment of cancer patients; moreover, the extrusion of TKIs by multidrug transporters may result in tumor cell TKI resistance. Interaction with multidrug resistance ABC transporters may also significantly modify the pharmacokinetics and toxicity of TKIs in patients.

Introduction

The tyrosine kinase (TK) signaling pathways regulate diverse physiological responses, including proliferation, differentiation, cell motility, and survival. However, these pathways are also utilized to promote tumor growth in a variety of cancers (Fig. 1). Much effort has been expended to develop specific TK inhibitors in order to prevent cancer. The two most promising therapeutic approaches make use of monoclonal antibodies and small molecule inhibitors that specifically target the tyrosine kinase enzymatic activity (Rowinsky, 2003, Vlahovic and Crawford, 2003).

Several small molecule TK inhibitors (TKIs) have been already introduced into clinical practice with significant effects in overcoming certain malignancies (Table 1). However, as usually found for anticancer agents, a variety of resistance phenotypes have been observed.

In the present review we summarize recent information concerning resistance to TKI-based drugs with respect to the function and overexpression of ABC multidrug transporters. The information presented may help in determining the proper dosing of TKIs in order to obtain optimum cellular kinase modulation, as well as to consider the possible effects of ABC multidrug transporters in the absorption, distribution, metabolism, and toxicity (ADME-Tox) of the TKIs, even before entering clinical development.

Section snippets

Tyrosine kinase inhibitors in cancer treatment

Protein tyrosine kinases form a large and diverse multigene family. The members of this family are involved in regulating cell-to-cell signaling, growth, differentiation, motility, changes in cell shape, and adhesion. Deregulation of tyrosine kinase activity has been demonstrated to play a significant role in disease development, including congenital syndromes, diabetes and cancer. In fact, about one third of oncogenes involved in most forms of human malignancies are derived from tyrosine

Tumor resistance to TKIs

Much of TKI drug development is in a relatively early phase, thus clinical resistance mechanisms could not have been explored in detail. Several cellular mechanisms were suggested to affect TKI tumor response, ranging from the amplification of the target receptor expression, impaired binding of TKIs as a consequence of receptor mutations, and a decreased TKI uptake into the tumor cells. Other resistance mechanisms may include the use of alternative pathways of cell activation or a constitutive

The ABC multidrug transporters in cancer drug resistance

The ABC family is one of the largest groups of transmembrane proteins consisting of 49 human members. A common, characteristic feature of ABC proteins is the specific ABC (ATP-Binding Cassette) domain that is responsible for ATP binding and hydrolysis. ABC proteins are present in all living species and can function both as receptors, channels, and transporters (Ueda et al., 1999). For receptors and channels, ATP binding and/or hydrolysis has a regulatory function, while in case of active ABC

Interactions of TKIs with ABC multidrug transporters—special role of ABCG2

The effectiveness of specific tyrosine kinase inhibitors, as discussed above, can be decreased due to mutations occurring in their target molecules, amplification of the target gene, or due to the activity of ABC transporters that can prevent TKIs from reaching their intracellular targets through drug extrusion.

Conclusions and future perspectives

Upregulation or aberrant activity of receptor tyrosine kinases can lead to tumor formation. Several specific tyrosine kinase inhibitors, like Gleevec, Iressa and Tarceva, have been successfully used in cancer treatment. However, there are subsets of tumors that do not respond to TKI treatment. This resistance may be due to the drug extrusion activity of multidrug resistance ABC transporters, especially of ABCG2. The multidrug transporters are present in many of our tissues with barrier

Acknowledgments

This work has been supported by research grants from OTKA, ETT and OM, Hungary (T35126, T31952, T35926, T38337, ETT, and NKFP). Csilla Özvegy-Laczka is a grantee of the Postdoctoral Fellowship (D 45957) of OTKA, Hungary and the János Bolyai Scholarship of the Hungarian Academy of Sciences. Balázs Sarkadi is a recipient of a Howard Hughes International Scholarship.

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