Promise of vandetanib, a FDA-approved RET kinase inhibitor, for the treatment of RET fusion-positive lung adenocarcinoma

The advent of precision lung cancer medicine, involving the treatment of tumors with EGFR and ALK oncogene aberrations with drugs that inhibit EGFR and ALK kinase activities, respectively, is potentially transformative for lung cancer patients. In 2012, oncogenic fusion of the RET gene, a driver of thyroid carcinogenesis, was re-discovered in a small subset of lung cancer by several groups (1-3). In-flame fusion of the RET tyrosine kinase gene with kinesin family member 5B (KIF5B) or coiled-coil domain containing 6 (CCDC6) genes, resulting in constitutive activation of the RET oncogene product, was identified as a novel oncogenic aberration in 1–2% of non-small cell carcinomas (NSCLCs), mainly in those with a histology of lung adenocarcinoma (LADC). These and a subsequent study demonstrated that the RET fusion gene has tumor-driving activity in vitro and in vivo (1-4). Up to now, a few other genes, including nuclear-receptor coactivator 4 (NCOA), tripartite-motif containing 33 (TRIM33), cutlike homeobox 1 (CUX1), KIAA1468 and KIAA1217 [also known as SKT, the human homolog of murine Skt (Sickle tail)], have been identified as other fusion partners of RET in NSCLC patients (5,6). In all these RET fusions, the coiled-coil domains of the partner proteins induce dimerization of the RET fusion protein, resulting in constitutive activation of RET kinase. The KIF5B-RET fusion is specific to lung cancer, while the CCDC6-RET fusion or the NCOA-RET fusion is common to both lung and thyroid cancers. RET fusions tend to be detected in young, female, and/or never/light-smoker patients with NSCLC (2,3,7-9)