Inhibition of RET Activated Pathways: Novel Strategies for Therapeutic Intervention in Human Cancers

Libero      Santarpia; Giulia      Bottai

doi:10.2174/1381612811306050864

Abstract

The REarranged during Transfection (RET) proto-oncogene and its activated signalling pathways have been shown to play an important role in cancer. RET genetic alterations including germline, somatic mutations and gene rearrangements have been demonstrated in several solid tumours, and numerous clinical trials using multikinase inhibitors containing RET as a target have shown significant activity against RET. Sorafenib and sunitinib have been approved for the treatment of renal, hepatocellular, gastrointestinal and pancreatic neuoendocrine carcinomas. Vandetanib has recently been approved for the treatment of unresectable locally advanced or metastatic medullary thyroid carcinomas. Novel genomic rearrangements and RET signalling interactions are now being studied in a variety of tumours and will provide the basis for new therapeutic strategies. Combination or sequential targeted therapies that are based on solid preclinical data regarding the inhibition of RET-mediated parallel or different -signalling pathways will likely be more effective.

Keywords: RET proto-oncogene, cancer, RET-activated signalling pathways, RET interacting proteins, tyrosine kinase inhibitors, targeted therapies, clinical trials, therapeutic strategies, sorafenib, sunitinib