Cell Culture Modeling of Genotype-Directed Sensitivity to Selective Kinase Inhibitors: Targeting the Anaplastic Lymphoma Kinase (ALK)

Abstract

Selective kinase inhibitors have emerged as an important class of cancer therapeutics. The clinical success of drugs such as imatinib, erlotinib, and lapatinib, together with findings demonstrating the important relationship between specific tumor genotypes and clinical response to these agents, also has brought to the forefront the concept of "personalized cancer medicine." The potential broader significance of this relationship has been further highlighted in preclinical studies using tumor-derived cell lines as a model system that can faithfully recapitulate the association of specific genotypes with drug sensitivity, suggesting the utility of cancer cell lines to identify novel candidate biomarkers for predicting clinically responsive patient subsets for newly developed anticancer agents. The case of the anaplastic lymphoma kinase (ALK) nicely exemplifies this, and cell line profiling has revealed that ALK mutations present in a subset of anaplastic large cell lymphomas (ALCLs), non-small cell lung cancers (NSCLCs), and neuroblastomas appear to sensitize cancer cells to treatment with selective ALK kinase inhibitors. Such findings suggest that genotype-based stratification of cancer patients for treatment with selective kinase inhibitors, even across multiple diseases of distinct tissue origin, may be essential for maximizing their clinical benefit.