Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes

• Published in: Nature reviews. Clinical oncology Vol. 15; no. 3; pp. 151 - 167
• Main Authors: Drilon, Alexander, Hu, Zishuo I., Lai, Gillianne G. Y., Tan, Daniel S. W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2018; Nature Publishing Group
• Subjects: 692/699/67/1059/602; 692/699/67/1459/1843; 692/699/67/1612/1350; 692/699/67/395; 692/700/565/1436/2185; Anaplastic Lymphoma Kinase - genetics; Carcinogenesis; Carcinogenesis - genetics; Epidermal growth factor receptors; ErbB Receptors - genetics; Gene mutation; Gene Rearrangement - genetics; Genetic aspects; Health aspects; Humans; Medicine & Public Health; Molecular Targeted Therapy; Mutation; Neoplasms - drug therapy; Neoplasms - genetics; Oncogenes; Oncology; Patients; Protein-tyrosine kinase; Protein-Tyrosine Kinases - genetics; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins c-ret - antagonists & inhibitors; Proto-Oncogene Proteins c-ret - genetics; Proto-Oncogene Proteins c-ret - therapeutic use; Regulatory approval; Ret protein; review-article; Solid tumors; Thyroid; Tumorigenesis; Tumors
• ISSN: 1759-4774; 1759-4782
• DOI: 10.1038/nrclinonc.2017.175

Key Points Activating alterations of the RET kinase are therapeutically actionable oncogenic drivers across a variety of cancers; in-frame RET rearrangements occur in subsets of non-small-cell lung and papillary thyroid cancers, and germ-line or somatic RET mutations are enriched in medullary thyroid cancers Confirmed and durable responses to multikinase inhibitors with activity against RET can be achieved in a proportion of patients with RET -rearranged or RET -mutant cancers; however, objective response rates are modest The outcomes observed with RET-directed therapy in RET -rearranged or RET -mutant cancers might be explained, in part, by the limitations of multikinase inhibitors, with inhibition of other kinases resulting in 'off-target' toxicities that preclude optimal dosing Novel approaches to RET-directed targeted therapy are currently being explored; potent and specific RET inhibitors with minimal preclinical off-target activity are being evaluated in early stage clinical trials, as are combination therapies Salient to the clinical development of potent RET inhibitors for patients of all ages, selective RET inactivation can affect the nervous, genitourinary, gastrointestinal, and haematopoietic systems during early development, but in adulthood, it leads to mild phenotypes The receptor-tyrosine kinase RET has been identified as a potentially actionable driver of oncogenesis. Several multikinase inhibitors with activity against RET have been explored in the clinic, but have only modest efficacy in patients with thyroid cancers, mostly in those with RET mutations, or RET -rearranged lung cancers. Herein, the authors outline the aberrations in RET that contribute to tumorigenesis, review the current clinical data for inhibitors of this kinase, and discuss whether the limited clinical success achieved with these agents to date is attributable to the intractability of RET as a drug target or the lack of highly specific RET inhibitors. The gene encoding the receptor-tyrosine kinase RET was first discovered more than three decades ago, and activating RET rearrangements and mutations have since been identified as actionable drivers of oncogenesis. Several multikinase inhibitors with activity against RET have been explored in the clinic, and confirmed responses to targeted therapy with these agents have been observed in patients with RET -rearranged lung cancers or RET -mutant thyroid cancers. Nevertheless, response rates to RET-directed therapy are modest compared with those achieved using targeted therapies matched to other oncogenic drivers of solid tumours, such as sensitizing EGFR or BRAF V600E mutations, or ALK or ROS1 rearrangements. To date, no RET-directed targeted therapeutic has received regulatory approval for the treatment of molecularly defined populations of patients with RET -mutant or RET -rearranged solid tumours. In this Review, we discuss how emerging data have informed the debate over whether the limited success of multikinase inhibitors with activity against RET can be attributed to the tractability of RET as a drug target or to the lack, until 2017, of highly specific inhibitors of this oncoprotein in the clinic. We emphasize that novel approaches to targeting RET-dependent tumours are necessary to improve the clinical efficacy of single-agent multikinase inhibition and, thus, hasten approvals of RET-directed targeted therapies.