Molecular determinants of response to RTK-targeting agents in nonsmall cell lung cancer.

Receptor tyrosine kinases (RTKs) are essential components of the cellular signaling apparatus and are often mutated or otherwise deregulated in nonsmall cell lung cancer (NSCLC). These receptors are not solely expressed by cancer cells but also by multiple other cell types, including stromal cells that, in turn, may modulate cancer cell functions by various direct and indirect interactions. Recently, clinical studies have successfully evaluated the inhibition of RTKs by specific RTK-targeting agents, including tyrosine kinase inhibitors (TKIs). Although the response was impressive in some studies, only a limited proportion of patients benefit from these new drugs. Therefore, an intensive search for markers has started to determine which patients and tumor types are most likely to respond favorably to this new kind of treatment. Considerable attention has been focused onto molecular changes in cancer cells such as receptor expression, gene amplification, changes in intracellular signaling and receptor mutations. In this article, we explore the current data regarding molecular alterations as surrogate markers of response to specific RTK-targeting agents in NSCLC. Defined alterations may serve as key markers helping to preselect NSCLC patients for an individualized therapeutic approach in the future. Copyright 2006 Wiley-Liss, Inc.