Ability to Acquire Drug Resistance Arises Early during the Tumorigenesis Process

Ernesto YagüE,Selina Raguz,Caroline M Ogilvie,LoïC Kubitza,Michael O'Hare,Christopher F Higgins,Parmjit Jat,Ian R Hart,Ana Arance

doi:10.1158/0008-5472.can-06-2574

Abstract

Resistance to chemotherapy is one of the principal causes of cancer mortality and is generally considered a late event in tumor progression. Although cellular models of drug resistance have been useful in identifying the molecules responsible for conferring drug resistance, most of these cellular models are derived from cell lines isolated from patients at a late stage in cancer progression. To ask at which stage in the tumorigenic progression does the cell gain the ability to acquire drug resistance, we generated a series of pre-tumorigenic and tumorigenic cells from human embryonic skin fibroblasts by introducing, sequentially, the catalytic subunit of telomerase, SV40 large T and small T oncoproteins, and an oncogenic form of ras. We show that the ability to acquire multidrug resistance (MDR) can arise before the malignant transformation stage. The minimal set of changes necessary to obtain pre-tumorigenic drug-resistant cells is expression of telomerase and inactivation of p53 and pRb. Thus, the pathways inactivated during tumorigenesis also confer the ability to acquire drug resistance. Microarray and functional studies of drug-resistant pre-tumorigenic cells indicate that the drug efflux pump P-glycoprotein is responsible for the MDR phenotype in this pre-tumorigenic cell model.

Highlights

Cytotoxic drugs are used widely for the treatment of cancer
We have used the Hahn and Weinberg model of tumorigenesis to ask at which stage in the tumorigenic progression does the cell gain the ability to acquire drug resistance? We show that disruption of the tumor suppressors p53 and pRb is sufficient to enable cells to avoid drug-induced senescence and acquire the capacity to develop drug resistance
HTERT expression was a prerequisite for the development of tumorigenesis because we were unable to generate Embryonic skin fibroblasts (ESF)-derived cells transfected only with the SV40 large T antigen (SV40 LT) and SV40 small T antigen (SV40 ST) in the absence of hTERT coexpression

Summary

Introduction

Cytotoxic drugs are used widely for the treatment of cancer. Some tumor types, including pancreatic, renal, colon, and malignant melanoma, often respond poorly to first-line chemotherapy and are classified as intrinsically resistant. The majority of solid tumors, including breast, ovarian, and small cell lung cancers, respond to chemotherapeutic regimes. In a significant proportion of cases, cancerous cells reappear following initial treatments and no longer respond to further therapy leading to. Several factors contribute to the development of drug resistance. Pharmacologic factors include inadequate access of drug to the tumor cell in solid tumors, inadequate infusion rate or route of delivery, and drug metabolism and excretion. The cellular factors contributing to drug resistance have been intensively studied in model cells selected for resistance to cytotoxic agents in vitro. Mechanisms identified include decreased drug uptake into cells, activation of detoxifying enzymes (e.g., cytochrome P450), activation of DNA repair mechanisms, alterations in drug-induced apoptosis, and increased drug efflux due to overexpression of transporters, such as P-glycoprotein [1]

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