The right compound for the right target: tackling RET
Authors: J. Seoane, J. Capdevila
Journal: Annals of Oncology (2018)

The advance in the treatment of cancer is based on the study and deep knowledge of the disease. Specifically, the success of cancer precision medicine resides on the ability to identify the right therapeutic target and develop specific and efficacious drugs. Clinical benefit has been achieved with targeted therapies such as ABL1 tyrosine-kinase inhibitors (TKI) in BCR-ABL1-rearranged chronic myeloid leukemia; EGFR, ALK, and ROS1 TKIs in EGFR-mutant, ALK rearranged, and ROS1 TKIs in non-small-cell lung cancers (NSCLCs), respectively; and BRAF and MEK inhibitors in BRAF-mutant melanomas and NSCLCs. In all cases, regulatory approval of the therapeutic agents has been achieved for the treatment of patients with advance-stage disease. As in the previously mentioned cases, the receptor tyrosine kinase RET exhibits all the right characteristics to be considered a good therapeutic target [1.Drilon A. Hu Z.I. Lai G.G.Y. Tan D.S.W. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes.Nat Rev Clin Oncol. 2017; 15: 150.Crossref PubMed Scopus (27) Google Scholar]. RET fusion and mutant proteins transform primary cells and activate downstream signaling pathways in a ligand-independent manner. RET genomic alterations promote cell proliferation and survival and generate carcinomas in genetically engineered mouse models. Moreover, RET alterations occur in a mutually exclusive pattern with other oncogenic drivers. However, despite being an appealing therapeutic target, response rates in RET-driven tumors are inferior to the ones observed in other cases of bona fide therapeutic targets such as ABL1, EGFR, ALK or ROS1. Why cannot we observe a good therapeutic response in RET-driven tumors? The answer resides in the characteristics of the pharmacological compounds used until now. Some multikinase inhibitors are being used for the treatment of RET-driven malignancies [2.Wells Jr, S.A. Robinson B.G. Gagel R.F. et al.Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial.J Clin Oncol. 2012; 30: 134-141Crossref PubMed Scopus (1045) Google Scholar, 3.Elisei R. Schlumberger M.J. Muller S.P. et al.Cabozantinib in progressive medullary thyroid cancer.J Clin Oncol. 2013; 31: 3639-3646Crossref PubMed Scopus (787) Google Scholar, 4.Drilon A. Rekhtman N. Arcila M. et al.Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial.Lancet Oncol. 2016; 17: 1653-1660Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar, 5.Lee S.H. Lee J.K. Ahn M.J. et al.Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial.Ann Oncol. 2017; 28: 292-297Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 6.Yoh K. Seto T. Satouchi M. et al.Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial.Lancet Respir Med. 2017; 5: 42-50Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar]. These compounds exhibit varying potencies against wild-type RET, RET rearrengements and RET mutations, and in some cases they do not show activity against V804M/L mutations (called gatekeeper mutations) described to confer resistance to multikinase inhibitors. Moreover, multikinase inhibitors are characterized by substantial off-target activity and can affect EGFR, MET, KIT, BRAF and VEGFR2. This can confound the contribution of RET inhibition to the antitumor effect of the drug and, moreover, the off-target inhibition can generate adverse events and toxicity through targeting non-RET kinases such as VEGFR2 [7.Hayman S.R. Leung N. Grande J.P. Garovic V.D. VEGF inhibition, hypertension, and renal toxicity.Curr Oncol Rep. 2012; 14: 285-294Crossref PubMed Scopus (158) Google Scholar, 8.Azad N.S. Aragon-Ching J.B. Dahut W.L. et al.Hand-foot skin reaction increases with cumulative sorafenib dose and with combination anti-vascular endothelial growth factor therapy.Clin Cancer Res. 2009; 15: 1411-1416Crossref PubMed Scopus (131) Google Scholar]. Subbiah et al. [9.Subbiah V. Velcheti V. Tuch B.B. et al.Selective RET kinase inhibition for patients with RET-altered cancers.Ann Oncol. 2018; 29: 1869-1876Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar] try to solve these problems through the generation of highly potent and selective RET inhibitors. In his work, Subbiah et al. [9.Subbiah V. Velcheti V. Tuch B.B. et al.Selective RET kinase inhibition for patients with RET-altered cancers.Ann Oncol. 2018; 29: 1869-1876Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar] showed that a novel and selective RET inhibitor, LOXO-292, was effective in inhibiting RET fusions and missense mutations including the RET V804M gatekeeper mutation. They used several types of preclinical models to test the efficacy of LOXO-292 including human cell lines harboring endogenous RET alterations or engineered to express mutant RET and, importantly, patient-derived xenografts (PDX). PDX models recapitulate the characteristics of the tumor of the patient and are optimal preclinical models for the study of pharmacological compounds [10.Byrne A.T. Alferez D.G. Amant F. et al.Interrogating open issues in cancer precision medicine with patient-derived xenografts.Nat Rev Cancer. 2017; 17: 254-268Crossref PubMed Scopus (421) Google Scholar, 11.Hidalgo M. Amant F. Biankin A.V. et al.Patient-derived xenograft models: an emerging platform for translational cancer research.Cancer Discov. 2014; 4: 998-1013Crossref PubMed Scopus (1067) Google Scholar]. Moreover, they were able to treat two patients with tumors harboring RET genomic alterations that were resistant to multikinase inhibitors. Interestingly, a rapid, intrapatient, pharmacokinetics-guided dose-escalation was carried out. This is important for the rapid development of highly specific, molecularly driven compounds exhibiting low toxicity, with particular interest in rare tumors and low incidence genomic alterations. Clinical responses were observed in both patients. One patient had an RET M918T-mutant medullary thyroid cancer metastatic to the liver that had acquired the RET V804M gatekeeper resistance mutation and had undergone six regimens with multikinase inhibitors. This patient experienced a confirmed tumor response upon treatment concomitant to rapid reductions in tumor calcitonin, CEA and cell-free circulating tumor DNA. The other patient had a lung cancer with a KIF5B-RET rearrangement and resistance to a multikinase inhibitor. The patient also had brain metastases that responded to treatment. Interestingly, similar results have been shown using a different highly selective inhibitor, Blu-667 [6.Yoh K. Seto T. Satouchi M. et al.Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial.Lancet Respir Med. 2017; 5: 42-50Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 12.Subbiah V. Gainor J.F. Rahal R. et al.Precision targeted therapy with BLU-667 for RET-driven cancers.Cancer Discov. 2018; Crossref PubMed Scopus (238) Google Scholar]. In that case, the authors showed that Blu-667 was more potent against RET than multikinase inhibitors and did not inhibit VEGFR2. The authors also treated patients with RET genomic alterations obtaining durable clinical responses [12.Subbiah V. Gainor J.F. Rahal R. et al.Precision targeted therapy with BLU-667 for RET-driven cancers.Cancer Discov. 2018; Crossref PubMed Scopus (238) Google Scholar]. The only prior partial response reported was using another RET inhibitor currently under development, RXDX-105 [13.Li G.G. Somwar R. Joseph J. et al.Antitumor activity of RXDX-105 in multiple cancer types with RET rearrangements or mutations.Clin Cancer Res. 2017; 23: 2981-2990Crossref PubMed Scopus (57) Google Scholar, 14.McNeil D. O'Driscoll J. Patel J. et al.Utilization of an innovative tool to improve oncology patient outcomes.J Clin Oncol. 2016; 34: 231Crossref Google Scholar]. Despite the high affinity of RXDX-105 against RET M918T mutation, the compound is significantly less potent inhibiting the RET V804M mutation highlighting the relevance of wide spectrum RET inhibition to avoid emerging resistant mutations (Table 1) [12.Subbiah V. Gainor J.F. Rahal R. et al.Precision targeted therapy with BLU-667 for RET-driven cancers.Cancer Discov. 2018; Crossref PubMed Scopus (238) Google Scholar, 15.BB Brandhuber, J Haas, BB Tuch et al. ENA-0490 The development of LOXO-292, a potent, KDR/VEGFR2-sparing RET kinase inhibitor for treating patients with RET-dependent cancers. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 2016; Poster #441.Google Scholar].Table 1Biochemical potency of RET inhibitors and MKIs against RET mutants and VEGFR2CompoundBiochemical IC50 (nM)WT RETRET V804MRET M918TVEGFR2LOXO-2920.40.80.7100BLU-6670.40.40.435RXDX-1053102417Cabozantinib1116282Vandetanib472674 Open table in a new tab All compounds currently under development show high activity and selectivity against wild-type and mutant RET when compared with multikinase inhibitors. However, slightly differences in affinity can be observed and may have an impact in efficacy and also toxicity at high doses (Table 1). The work of Subbiah et al. opens a novel avenue in the treatment of RET-dependent tumors. The specificity and potency of LOXO-292, and other RET selective compounds, and its preliminary antitumor activity in patients in addition to its seemingly favorable clinical safety profile indicate that these types of compounds may improve the outcomes of RET-dependent cancer patients. The low off-target effect of these compounds might allow dose-dense treatments to ensure long-term target engagement without toxicity, maintaining efficacy and quality of life (Figure 1). Importantly, promising results have recently been shown in a larger cohort of patients included in the phase I clinical trial of LOXO-292. In RET-altered cancers, objective responses were reported in 77% of cases with fusion alterations and 45% in RET-mutant medullary thyroid cancers, regardless drug dose level, prior therapies and RET mutation and fusion partners [16.Drilon A.E. Subbiah V. Oxnard G.R. et al.A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers.J Clin Oncol. 2018; 36: abstr 102Crossref Google Scholar]. RET could then be comparable to other targetable genes such as ABL1, EGFR, ALK or ROS1. More work is warranted and full clinical trials have to be conducted, but the data so far look promising and appealing. Once again the in-depth study of cancer and the identification of solid therapeutic targets and good pharmacological compounds bear its fruits in the fight against cancer. This study was funded by the Asociación Española contra el Cáncer (AECC), the FIS PI16/01278 and the FERO and Cellex foundations.