Identifying novel oncogenic <i>RET</i> mutations and characterising their sensitivity to RET-specific inhibitors.

Abstract

Rearranged during transfection (<i>RET</i>) is a well-known proto-oncogene. Multiple <i>RET</i> oncogenic alterations have been identified, including fusions and mutations. Although <i>RET</i> fusions have been reported in multiple cancers, <i>RET</i> mutations were mainly found in multiple endocrine neoplasia type 2 and medullary thyroid carcinoma. <i>RET</i> mutations in other cancers were underinvestigated and their functional annotation was less well studied. We retrospectively reviewed next-generation sequencing data from 37 056 patients with cancer to search for <i>RET</i> mutations. We excluded patients with other co-occurring known driver mutations to enrich potential activating <i>RET</i> mutations for further analysis. Moreover, we performed in vitro functional validation of the oncogenic property of several high frequent and novel <i>RET</i> mutants and their sensitivity to RET-specific inhibitors LOXO-292 and BLU-667. Within 560 (1.5%) patients with cancer who harbour <i>RET</i> mutations, we identified 380 distinct <i>RET</i> mutation sites, including 252 sites without co-occurring driver mutations. <i>RET</i> mutations were more frequently found in thyroid cancer, mediastinal tumour and several other cancers. The mutation sites spread out through the whole protein with a few hotspots within the kinase domain. In addition, we functionally validated that 898-901del, T930P and T930K were novel <i>RET</i>-activating mutations and they were all sensitive to RET inhibitors. Our results demonstrated the frequency of <i>RET</i> mutations across different cancers. We reported and/or validated several previously uncharacterised <i>RET</i> oncogenic mutations and demonstrated their sensitivity to RET-specific inhibitors. Our results help to stratify patients with cancer based on their <i>RET</i> mutation status and potentially provide more targeted treatment options.