A genomic signature of chemotherapeutic multidrug resistance provides a rational approach to identify patients for targeted therapy in advanced solid tumors

Abstract

10613 Background: Multidrug resistance (MDR), the process by which cells resist many structurally and functionally unrelated drugs, remains a major challenge for cancer treatment. Strategies to reliably predict MDR will revolutionize cancer therapy. Methods: We made use of in vitro drug sensitivity data on 47 FDA approved chemotherapeutic agents from the NCI-60 database coupled with Affymetrix microarray data, to develop a gene expression signature of chemotherapeutic MDR, using a 'metagene’ approach to gene expression analysis (Potti et al, Nature Medicine, 2006). The capacity of the MDR signature to predict in vitro and in vivo resistance was evaluated in multiple independent cell line and patient cohorts. Results: A gene expression signature of chemotherapeutic MDR developed from cancer cell lines using a novel ‘metagene’ approach can accurately predict patients resistant to standard chemotherapeutic agents, including multi-drug regimens. This includes cohorts of patients with early stage breast cancer (n = 171; accuracy: 75.5%, sensitivity: 49.3%, specificity: 92%), patients who received neoadjuvant chemotherapy (n = 51; accuracy: 78.5%, sensitivity: 73.7%, specificity: 92.3%), and ovarian cancer (n = 105; accuracy: 83.8%, sensitivity: 71.8%, specificity: 93.7%). We further show that MDR signature expression is an independent prognostic factor in early stage breast cancer (p = 0.02, odds ratio: 3.49) and a large cohort of non-small cell lung cancer (p = 0.03, odds ratio: 5.70), in a multivariate analysis. Finally, to identify a rational therapeutic strategy in patients with the MDR phenotype, we have integrated the prediction of MDR with profiles of oncogenic pathway deregulation (Bild A, Nature, 2006) and show that targeting the Src pathway using a Src specific inhibitor (SU6656) circumvents MDR in the in vitro setting. Conclusions: The development of a gene expression signature of MDR, that can predict resistance to commonly used cytotoxic chemotherapies, provides a rational approach to developmental therapeutics, by identifying novel 'customized’ candidate drugs (e.g. targeting Src) for further clinical development. No significant financial relationships to disclose.