Receptor tyrosine kinases as therapeutic targets in rhabdomyosarcoma

Abstract

Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas of childhood and adolescence. To date, there are no effective treatments that target the genetic abnormalities in RMS, and current treatment options for high-risk groups are not adequate. Over the past two decades, research into the molecular mechanisms of RMS has identified key genes and signaling pathways involved in disease pathogenesis. In these studies, members of the receptor tyrosine kinase (RTK) family of cell surface receptors have been characterized as druggable targets for RMS. Through small molecule inhibitors, ligand-neutralizing agents, and monoclonal receptor-blocking antibodies, RTK activity can be manipulated to block oncogenic properties associated with RMS. Herein, we review the members of the RTK family that are implicated in RMS tumorigenesis and discuss both the problems and promise of targeting RTKs in RMS.

Figure 1

Rationale for dual treatment targeting the IGF-1R signaling pathway in RMS. Rapamycin inhibits mTOR signaling, preventing inhibitory feedback on IRS-1 which allows proliferative signals from IGF-1R to IRS-1, PI3K, and AKT. Dual treatment using rapamycin in combination with IGF-1R inhibition, such as monoclonal blocking antibodies, prevents signaling to these critical progrowth signaling nodes.

Figure 2

RTKs associated with RMS and their known roles in RMS tumorigenesis or progression.