Breast cancer (BC) is the most common malignancy in women. It is classified into a few major molecular subtypes according to hormone and growth factor receptor expression. Over the past few years, substantial advances have been made in the discovery of new drugs for treating BC. Improved understanding of the biologic heterogeneity of BC has allowed the development of more effective and individualized approach to treatment. In this review, we provide an update about the current treatment strategy and discuss the various emerging novel therapies for the major molecular subtypes of BC. A brief account of the clinical development of inhibitors of poly(ADP-ribose) polymerase, cyclin-dependent kinases 4 and 6, phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, histone deacetylation, multi-targeting tyrosine kinases, and immune checkpoints for personalized treatment of BC is included. However, no targeted drug has been approved for the most aggressive subtype—triple negative breast cancer (TNBC). Thus, we discuss the heterogeneity of TNBC and how molecular subtyping of TNBC may help drug discovery for this deadly disease. The emergence of drug resistance also poses threat to the successful development of targeted therapy in various molecular subtypes of BC. New clinical trials should incorporate advanced methods to identify changes induced by drug treatment, which may be associated with the upregulation of compensatory signaling pathways in drug resistant cancer cells.

Apatinib, a small-molecule multitargeted tyrosine kinase inhibitor, is in phase III clinical trial for the treatment of patients with non–small-cell lung cancer and gastric cancer in China. In this study, we determined the effect of apatinib on the interaction of specific antineoplastic compounds with P-glycoprotein (ABCB1), multidrug resistance protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2). Our results showed that apatinib significantly enhanced the cytotoxicity of ABCB1 or ABCG2 substrate drugs in KBv200, MCF-7/adr, and HEK293/ABCB1 cells overexpressing ABCB1 and in S1-M1-80, MCF-7/FLV1000, and HEK293/ABCG2-R2 cells overexpressing ABCG2 (wild-type). In contrast, apatinib did not alter the cytotoxicity of specific substrates in the parental cells and cells overexpressing ABCC1. Apatinib significantly increased the intracellular accumulation of rhodamine 123 and doxorubicin in the multidrug resistance (MDR) cells. Furthermore, apatinib significantly inhibited the photoaffinity labeling of both ABCB1 and ABCG2 with [¹²⁵I]iodoarylazidoprazosin in a concentration-dependent manner. The ATPase activity of both ABCB1 and ABCG2 was significantly increased by apatinib. However, apatinib, at a concentration that produced a reversal of MDR, did not significantly alter the ABCB1 or ABCG2 protein or mRNA expression levels or the phosphorylation of AKT and extracellular signal–regulated kinase 1/2 (ERK1/2). Importantly, apatinib significantly enhanced the effect of paclitaxel against the ABCB1-resistant KBv200 cancer cell xenografts in nude mice. In conclusion, apatinib reverses ABCB1- and ABCG2-mediated MDR by inhibiting their transport function, but not by blocking the AKT or ERK1/2 pathway or downregulating ABCB1 or ABCG2 expression. Apatinib may be useful in circumventing MDR to other conventional antineoplastic drugs. Cancer Res; 70(20); 7981–91. ©2010 AACR.