The Biology Behind Is KIT an Important Therapeutic Target in Small Cell Lung Cancer?

Introduction SCLC represents a significant minority of lung cancer (15–25%) and typically presents as extensive-stage disease. Although SCLC is highly responsive to cisplatin-based combination chemotherapy, most patients have disease recurrence and few patients are cured. A plateau in the development of effective medical therapy for this difficult cancer has led to a search for new active agents (1). In this issue, Johnson et al. (2) report on their efforts to clinically target the KIT RTK in SCLC using imatinib (formerly STI571; Gleevec in the United States and Glivec in Europe; Novartis Pharma, Basel, Switzerland) . The goal of this commentary will be to review the rationale for this novel therapeutic approach. KIT is a Mr 145,000 transmembrane glycoprotein that serves as the receptor for KITLG (also known as stem cell factor, mast cell growth factor, Steel factor) and has intrinsic tyrosine kinase activity. A member of the large family of RTKs, KIT is closely related to the receptors for PDGF, colony stimulating factor 1, and FMS-related tyrosine kinase 3-ligand. Binding of KITLG to KIT results in receptor homodimerization and the activation of tyrosine kinase activity, leading to phosphorylation of a variety of signaling intermediates. In many cases, these substrates are themselves kinases and serve to initiate and/or amplify intracellular signal transduction. KIT is critical to the development of the ICC, hematopoietic progenitor cells, mast cells, melanocytes, and germ cells. Not surprisingly, many of the KIT-expressing cells in adults are the same cells that have a developmental requirement for normal functional activity of KIT. Specifically, KIT is normally expressed by germ cells, mast cells, ICC, melanocytes, and certain hematopoietic progenitors. KIT is also expressed by a variety of neoplasms, including some neoplasms that arise from cell types that normally express KIT (e.g., ICC3GISTs). In addition, KIT is expressed by a variety of neoplasms, including SCLC, whose putative cells of origin are not developmentally dependent on KIT (3). PDGF(RA), platelet derived growth factor (receptor A).