Tyrosine Kinase Networks in Pediatric Cancer
Understanding how childhood cancer cells respond to extra- or intracellular signals is key to identifying how signal transduction pathways might be specifically activated in tumor cells. Targeting of these pathways can then be used as a treatment strategy, while minimizing effects on normal growth. Central to cellular signaling pathways are protein kinases, which enzymatically link phosphate groups to tyrosine, serine, or threonine residues of substrate proteins, thus activating or inhibiting their functions. It is well established that receptor protein tyrosine kinases (PTKs) can be activated by mutations or over-expression in human tumors. Activated PTKs can then be targeted therapeutically, although additional mutations generated after treatment may lead to kinase inhibitor resistance. For example, relatively specific kinase inhibitors such as Gleevec for BCR-ABL, c-KIT, and PDGFR, and Iressa for EGFR have been developed and are in various stages of clinical trials. In pediatric cancer, targeting of the IGF1 receptor (IGF1R), SRC, and ALK in childhood solid tumors is currently under intense scrutiny.
What has become clear from studying these PTK inhibitors is that overall expression status of the respective tyrosine PTK is not the only important determinant for efficacy of kinase inhibitors, but that the activation state in a given tumor type is also a key parameter. Another factor that is emerging in this context is that activation of other PTKs leading to parallel activation of distal pathway elements common to the RTK being targeted may underlie resistance to inhibitors of the latter. Therefore, a detailed knowledge of PTK networks in tumor cells is essential for efficient use of PTK inhibitors in childhood cancer.