Overcoming ABC transporter-mediated multidrug resistance: The dual role of tyrosine kinase inhibitors as multitargeting agents

Abstract

Resistance to conventional and target specific antitumor drugs still remains one of the major cause of treatment failure and patience death. This condition often involves ATP-binding cassette (ABC) transporters that, by pumping the drugs outside from cancer cells, attenuate the potency of chemotherapeutics and negatively impact on the fate of anticancer therapy. In recent years, several tyrosine kinase inhibitors (TKIs) (e.g., imatinib, nilotinib, dasatinib, ponatinib, gefitinib, erlotinib, lapatinib, vandetanib, sunitinib, sorafenib) have been reported to interact with ABC transporters (e.g., ABCB1, ABCC1, ABCG2, ABCC10). This finding disclosed a very complex scenario in which TKIs may behave as substrates or inhibitors depending on the expression of specific pumps, drug concentration, affinity for transporters and types of co-administered agents. In this context, in-depth investigation on TKI chemosensitizing functions might provide a strong rationale for combining TKIs and conventional therapeutics in specific malignancies. The reposition of TKIs as antagonists of ABC transporters opens a new way towards anticancer therapy and clinical strategies aimed at counteracting drug resistance. This review will focus on some paradigmatic examples of the complex and not yet fully elucidated interaction between clinical available TKIs (e.g. BCR-ABL, EGFR, VEGFR inhibitors) with the main ABC transporters implicated in multidrug resistance.

Keywords: BCR-ABL inhibitors; Drug combinations; EGFR inhibitors; MDR; VEGFR inhibitors.