Optimizing targeted cancer therapy: Towards clinical application of systems biology approaches

Abstract

In cancer, genetic and epigenetic alterations ultimately culminate in discordant activation of signal transduction pathways driving the malignant process. Pharmacological or biological inhibition of such pathways holds significant promise with respect to devising rational therapy for cancer. Thus, technical concepts pursuing robust characterization of kinase activity in tissue samples from cancer patients have been subject of investigation. In the present review we provide a comprehensive overview of these techniques and discuss their advantages and disadvantages for systems biology approaches to identify kinase targets in oncological disease.

Recent advances in the development and application of array-based peptide-substrate kinase activity screens show great promise in overcoming the discrepancy between the evaluation of aberrant cell signaling in specific malignancies or even individual patients and the currently available ensemble of highly specific targeted treatment strategies. These developments have the potential to result in a more effective selection of kinase inhibitors and thus optimize mechanism-based patient-specific therapeutic strategies. Given the results from current research on the tumor kinome, generating network views on aberrant tumor cell signaling is critical to meet this challenge.

Introduction

Cancer is defined as an uncontrolled proliferation of clonally derived cells. This malignant transformation is characterized by changes in the expression and activity of key mediators of signal transduction coordinating proliferation, migration and cell death [1]. The tremendous significance of changes in cell signaling activity in the malignant transformation of cells has only been fully recognized in the last decade [2], [3], [4]. The identification of disease-related signal transduction effectors culminated into the acknowledgement of protein kinases as one of the most important classes of potential drug targets to date [5]. Significant advances in the development of small molecule inhibitors to counteract aberrant cell signaling promoting tumor cell proliferation have been made since then. Kinase signaling, because of the excellent specific drugability of the ATP-binding pocket, as well as the general importance in virtually all signal transduction pathways, holds great promise here. The first breakthrough was the approval of the Abl kinase inhibitor Imatinib for treatment of BCR-Abl positive chronic myeloid leukemia [6]. Application of this inhibitor is at present part of first-line treatment for chronic myeloid leukemia and has improved patient outcome dramatically.

Despite the successful application of kinase inhibitors for the treatment of specific malignancies, tumor resistance due to acquired mutations in downstream effectors of the targeted molecule and toxicities as a result of limited agent specificity remain important challenges to overcome [7], [8], [9], [10], [11], [12], [13]. Insufficient ways to predict the efficacy of inhibiting specific kinase activity gives rise to a discrepancy between the evaluation of aberrant cell signaling and the currently available ensemble of highly specific targeted treatment strategies. Hence, providing better ways to predict the efficacy of kinase-targeted small molecule inhibitors in the tumor- or patient-specific situation will be one of the most important goals of cancer research in the upcoming decade. Accurate identification of tumor type-specific or even patient-specific aberrations in cell signaling activity that are crucial for tumor progression, is required. In this review we provide an overview of recent developments in kinase activity screening concepts focused on achieving that goal. An introduction concerning aberrant protein kinase activity as the essence of the oncogenic phenotype will be followed by a discussion of the gap in knowledge on anomalous cell signaling in specific malignancies that is becoming ever more evident, thereby severely hampering the implementation of kinome-targeted cancer therapies. After a description of the most apparent challenges that have emerged in recent research, we will address the most encouraging strategies aimed at dissecting the cancer-specific signal transduction network. Promising research focused on allowing us to obtain a better grip on the selection of effective and specific kinome-targeted cancer treatment strategies will be evaluated. Future investigational topics will be discussed.