Targeting MDR in breast and lung cancer: discriminating its potential importance from the failure of drug resistance reversal studies

Abstract

This special issue of Drug Resistance Updates is dedicated to multidrug resistance protein 1 (MDR-1), 35 years after its discovery. While enormous progress has been made and our understanding of drug resistance has become more sophisticated and nuanced, after 35 years the role of MDR-1 in clinical oncology remains a work in progress. Despite clear in vitro evidence that P-glycoprotein (Pgp), encoded by MDR-1, is able to dramatically reduce drug concentrations in cultured cells, and that drug accumulation can be increased by small molecule inhibitors, clinical trials testing this paradigm have mostly failed. Some have argued that it is no longer worthy of study. However, repeated analyses have demonstrated MDR-1 expression in a tumor is a poor prognostic indicator leading some to conclude MDR-1 is a marker of a more aggressive phenotype, rather than a mechanism of drug resistance. In this review we will re-evaluate the MDR-1 story in light of our new understanding of molecular targeted therapy, using breast and lung cancer as examples. In the end we will reconcile the data available and the knowledge gained in support of a thesis that we understand far more than we realize, and that we can use this knowledge to improve future therapies.

Figure 1

FPAC imaging of a patient with breast cancer. Fused PET/CT (top row, axial and coronal views) and PET (bottom row, axial and coronal views) of a female patient with breast cancer 80 minutes after the injection of 6.1mCi ¹⁸F fluoropaclitaxel (FPAC). Right breast tumor (arrow) showing increased FPAC uptake (SUV of 1.3). Note absence of uptake in the brain due to the blood-brain-barrier (BBB) (a portion of the pituitary gland outside the BBB seen (solid arrow head)). Physiologic uptake in the heart, liver, bowel and bone marrow are also seen, as is residual tracer in the vasculature of the injected arm (brackets). Due to the extensive hepatic clearance and subsequent excretion into bowel, the diagnostic value of FPAC PET in the abdomen and pelvis is limited. A pilot study of FPAC PET in patients with a renal, adrenal, lung and breast cancer patients is ongoing (http://clinicaltrials.gov/ct2/show/NCT01086696).

Figure 2

The impact of ABC transporters on CNS uptake in murine knockout studies. Data from 6 separate studies were compiled to generate the bar graphs shown (de Vries et al., 2007; Kodaira et al., 2010; Lagas et al., 2010; Poller et al., 2011; Polli et al., 2009; Tang et al., 2012). All of the studies employed mice bearing knockout of ABCB1a/b, ABCG2, or both ABCB1a/b and ABCG2 mice. Brain concentrations were reported as relative to wild type and were measured at different timepoints – lapatinib, 24 h; topotecan, 24 h; mitoxantrone, 2 h; axitinib, 1 h; sorafenib, 6 h; and sunitinib, 6 h. Mitoxantrone data were expressed as Cbrain/Cplasma and estimated from Figure 4 in the reference (Kodaira et al., 2010), while topotecan data were reported as area under the concentration curve (AUC) (de Vries et al., 2007).