MDR1 inhibition: less resistance or less relevance?

The P-glycoprotein (P-gp) family of proteins promotes resistance to cytotoxic agents by increased efflux from within the cell [1]. Numerous clinical studies have correlated expression of MDR1, a P-gp homologue found in human tissues, with increased drug resistance and decreased clinical response in selected haematological malignancies and solid tumours [2,3]. Whether MDR1 is indeed functionally relevant to tumour drug resistance instead of a tantalising epiphenomenon remains uncertain; it is but one of many proteins implicated in the cellular response to chemotherapy. None the less, this protein has been targeted intensely in recent therapeutic strategies aimed at reversing the drug resistance phenotype [4,5]. With this in mind, Davidson and colleagues (this issue) have attempted to sensitise refractory solid tumours to cytotoxic chemotherapy through pharmacological modulation of MDR1 activity. These authors administered a modified EVE regimen (etoposide, vincristine, and epirubicin—each is a MDR1 substrate) along with high-dose cyclosporin, a well-known MDR1 inhibitor, to 16 paediatric patients whose tumours had progressed on therapy or shortly thereafter. The results were modest: two partial responses and 7 patients with short-lived disease stabilisation. Davidson and colleagues add to a growing literature examining MDR1 blockade, including several large clinical trials. Together with previous observations, these data highlight lingering questions regarding the efficacy and clinical relevance of this mechanism, while illustrating several principles and pitfalls of drug resistance modulation and target-based strategies in general. Before considering the clinical data on MDR1 modulation, it is useful to review some key concepts of the target validation process. At minimum, a ‘valid’ protein target must be: (1) expressed or induced in the cancer cells of interest; (2) physiologically active in the appropriate setting; and (3) relevant or limiting with respect to the mechanism being targeted. In clinical trials seeking to validate MDR1 as a drug resistance target, it would therefore seem necessary to confirm its presence and activity within tumours of the study population (this was not done in the Davidson study). To be sure, MDR1 clears such hurdles easily in the preclinical setting; indeed, it represents the principal multidrug-resistance factor in many in vitro systems and animal models [6,7]. At the same time, it is one member of a large family of potential drug resistance modulators ([8,9] Table 1). Other well-known processes (e.g. detoxifying enzymes, apoptosis factors, tumour microenvironment) may also play dominant roles in both intrinsic and acquired resistance [10–14]. Therefore, the validation of MDR1 as a clinical target is not an easy task. None the less, several clinical studies performed during the last decade provided strong evidence linking MDR1 expression and function to a poor response to chemotherapy, particularly in patients with acute myelogenous leukaemia (AML). For example, the Southwest Oncology Group (SWOG) performed both protein expression and functional drug efflux analysis on leukaemic blasts from 211 elderly patients, and found a striking inverse correlation between MDR1 activity and the complete response (CR) rate [2]. A similar study in younger AML patients found that only MDR1 activity, and not other candidate resistance mechanisms, correlated significantly with the CR rate [15]. These data seemed to validate criteria 1 and 2 above for MDR1 as a target for drug resistance reversal.