ABC transporters: unvalidated therapeutic targets in cancer and the CNS

Abstract

The discovery of the multidrug transporter P-glycoprotein (Pgp) over 35 years ago in drug resistant cells prompted several decades of work attempting to overcome drug resistance by inhibition of drug efflux. Despite convincing laboratory data showing that drug transport can be inhibited in vitro, efforts to translate this discovery to the clinic have not succeeded. Since overexpression of Pgp and related transporters including ABCG2 and members of the ABCC family have been linked with poor outcome, it remains a reasonable hypothesis that this poor outcome is linked to reduction of drug exposure by efflux, and thus to drug resistance. In this review, we will discuss the question of whether ABC transporters mediate drug resistance in cancer through a reduction in drug accumulation in tumors, and whether the "Pgp inhibition hypothesis" might be wrong. The hypothesis, which holds that increased chemotherapy effectiveness can be achieved by inhibiting Pgp-mediated drug efflux has only been validated in model systems. Possible explanations for the failure to validate this clinically include the existence of other modulators of drug accumulation and uptake in tumors. Despite these difficulties, a potential role has emerged for drug transporters as therapeutic targets in the central nervous system (CNS). Both lines of investigation point to the need for imaging agents to facilitate the study of drug accumulation in human cancer. This is a critical need for targeted therapies where an important dose-response relationship is likely to exist, and where drug resistance renders many of the novel targeted agents ineffective in a subset of patients.

Figure 1

Chemical structures of Pgp inhibitors

Figure 2

(A) From Pajic M et al. Cancer Res 2009;69:6396–6404: Doxorubicin-resistant Brca1−/−; p53−/− mammary tumors were generated in K14cre;Brca1F/F;p53F/F mice, and then orthotopically transplanted into syngeneic mice. The figure shows results following 10 mg tariquidar/kg i.v. (turquoise), 5 mg doxorubicin/kg i.v. (pink), or 10 mg tariquidar/kg i.v. followed 15 min later by 5 mg doxorubicin/kg i.v. (in three separate animals, shown in green, orange, and brown). Tumors were treated when the size reached ~200 mm3. (B) From Rottenberg S et al. PNAS 2008;105:17079–17084: Orthotopically transplanted mice were treated with 50 mg olaparib (AZD2281) per kg for 28 days. When tumors relapsed to 100%; of their original volume, they were retreated by i.p. injection of 2 mg of tariquidar per kg every other day (light blue line) or 50 mg of AZD2281 per kg daily (red line) or both (dark blue line). Relative tumor volume (RTV, ratio of tumor volume to initial size at start of treatment) is shown as a function of time.

Figure 3. From Zander S A et al. Cancer Res 2010;70:1700–1710

Overall survival (%;) over time of wild-type animals carrying orthotopically transplanted Abcg2-proficient or ABCG2-deficient Brca1−/−, p53−/− mammary tumors. Topotecan was administered at 4 mg/kg topotecan i.p. on days 0 to 4 and 14 to 18. When tumors relapsed or showed progression (tumor size, ≥50%), treatment was resumed.

Figure 4

Schematic illustrating the proportions of drug resistance factors needed to successfully exploit ABC transporters as therapeutic targets. In the schematic in panel A, reduced drug accumulation must be the most important component of drug resistance. Decreasing drug accumulation confers increasing levels of resistance while other mechanisms occupy a relatively minor role. In turn, in panel B, ABC efflux transporters are the major contributor of reduced drug accumulation. These assumptions, although never proven, underlay the hypothesis that inhibition of drug efflux could reverse drug resistance and improve drug efficacy.

Figure 5

Effects of ABC transporters on brain penetration of substrate compounds. The fold-increase in brain penetration of flavopiridol, imatinib, topotecan, dasatinib, lapatinib, and sorafenib was determined in mice lacking Abcb1a/b (Abcb1a/b −/−), Abcg2 (Abcg2 −/−) or both transporters (Abcb1a/b −/− Abcg2 −/−) compared to wild-type mice (WT) which were assigned a value of 1. Data compiled from [–55].