Last year the Food and Drug Administration approved two selective RET inhibitors for treatment of solid tumours with altered RET gene.
RET (REarranged during Transfection) gene encodes a transmembrane glycoprotein receptor with tyrosine kinase activity, which plays a fundamental role in many physiological functions like early embryogenesis, development of the enteric nervous system, kidney morphogenesis, spermatogenesis, hematopoiesis and potentially immunomodulation.
In recent years, increasing evidences show that aberrantly activated RET is a critical driver of tumor growth and proliferation across a broad spectrum of tumors.
Oncogenic activation of RET occurs mainly in two different ways: 1) chromosomal rearrangement giving rise to chimeric fusion genes and 2) somatic or germline mutations. These gain-of-function alterations lead to the constitutive activation of RET, either via ligand-independent dimerization or by aberrant expression or activation of monomeric receptors.
Somatic RET rearrangements consist of in-frame fusions of 5?-end of partner genes with the 3?-end of RET containing its kinase domain.
RET rearrangements are reported to occur in 5%-10% of sporadic Papillary Thyroid Cancers (PTC), of which >90% of cases harbour the CCDC6-RET or NCOA4-RET fusion genes, and in 1%-2% of Non-Small Cell Lung Cancer (NSCLC), where the most frequent fusion partner is KIF5B. In NSCLC RET rearrangements tend to be mutually exclusive with other major lung cancer driver alterations such as KRAS and EGFR mutations, ALK and ROS1 fusions and usually associate with low tumour mutation burden and low PD-L1 expression.