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

Abstract

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 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.

RET Gene Fusions in Malignancies of the Thyroid and Other Tissues

“…RET fusions occur in 1%-2% of lung carcinoma, predominantly in adenocarcinoma (LADC) but also in rare types such as adenosquamous carcinoma [13,17,18,29,[50][51][52][114][115][116]. In the same analysis of large databases described above, RET fusions were found in 0.35%-0.88% of LADC (n = 9088) [18].…”

“…Instead, RET fusions, occurring at the somatic level, are typical of papillary thyroid carcinoma, lung adenocarcinoma, and few other cancers. This notion has made RET an attractive molecular target for small molecule tyrosine kinase inhibitors (TKI) [11][12][13][14]. In this frame, novel selective RET TKIs have featured promising results in clinical investigation [14,15].…”

“…RET gene fusions are thought to occur secondary to DNA double-strand breaks (DSB) followed by illegitimate repair of the two unrelated genes [13,18,95,96]. DNA repair mechanisms that can be responsible include NHEJ (nonhomologous end joining), which requires no homology or just very short homology sequences and inserts a few nucleotides at the fusion point, and BIR (break-induced replication), that instead requires long homology DNA stretches [95,96].…”

The genomic imprint of cancer therapies helps timing the formation of metastases

“…The RET T791Y mutation was most interesting as it can trigger the ligand-independent activation of the RET receptor, thereby contributing to the activation of the JAK/STAT3 pathway. 27 Indeed, while the RET Y791F mutation was initially considered a low risk mutation, it was later reclassified as a likely non-pathogenic polymorphism. 27 Indeed, while the RET Y791F mutation was initially considered a low risk mutation, it was later reclassified as a likely non-pathogenic polymorphism.…”

“…26 Although RET activating mutations are widely found in thyroid cancers, only rearrangements of the RET gene are common in NSCLC. 27 Indeed, while the RET Y791F mutation was initially considered a low risk mutation, it was later reclassified as a likely non-pathogenic polymorphism. 28,29 Somatic mutagenesis across multiple metastases Patterns of somatic mutations in cancer genomes provide important information concerning tumour aetiology.…”