RESEARCH HIGHLIGHTS TARGETED THERAPY Ripretinib turns off the switch in GIST More than 85% of cases of type II kinase inhibitors such as gastrointestinal stromal tumour imatinib, regorafenib and sunitinib. (GIST) harbour mutations in the To develop a novel KIT and genes encoding the receptor tyrosine PDGFRα inhibitor that is designed kinases KIT and platelet-derived to inhibit activating mutations in growth factor receptor α (PDGFRα). all relevant known exons, including Treatment of metastatic GIST has in the activation loop, Flynn and been transformed by kinase inhibitors colleagues used structure-based drug such as imatinib, which is considered design to create an inhibitor that to be one of the most successful could bind to key amino acid residues targeted agents ever developed. within the KIT switching mechanism. Plus Images Bank/Getty Image Rosario/The M. Antonio Credit: However, this type of inhibitor In vitro, ripretinib and other only blocks a limited number analogues both prevented KIT from conducted a first-in-human study to of KIT mutants, and secondary adopting a type I active conformation evaluate the safety and tolerability resistance mutations eventually and locked it in the inactive of ripretinib (NCT02571036). emerge. Now, Daniel Flynn, from conformation. The authors showed Patients with drug-resistant GIST Deciphera Pharmaceuticals, that ripretinib inhibited mutations harbouring a broad spectrum of and collaborators have designed across all six exons known to be KIT mutations were enrolled during ripretinib, an investigational mutated in KIT-driven GIST as well the dose-escalation phase of study. tyrosine kinase inhibitor that targets as mutations in PDGFRα in a panel At first assessment, two representative a broad spectrum of KIT and of GIST cell lines and cells expressing patients in this phase I study showed PDGFRα mutants. primary and drug-resistant KIT reduction of KIT mutant allele “Kinases are known to have or PDGFRα mutants. Ripretinib frequency in circulating tumour DNA. embedded switches that regulate also inhibited proliferation of Ripretinib is currently being protein conformation and enzymatic KIT and PDGFRα mutant cell studied in two phase III trials: activity”, explains Flynn. KIT and lines derived from GIST, systemic INVICTUS and INTRIGUE in PDGFRα have two switches: an mastocytosis, leukaemia and lung patients with GIST. The results inhibitory switch in the intracellular cancer. “Furthermore, saturation from these trials could confirm juxtamembrane domain (JMD, mutagenesis studies revealed that the potential of this investigational which is encoded by exon 11 in ripretinib was able to withstand inhibitor. Furthermore, the switch KIT and exon 12 in PDGFRA) and emergence of de novo KIT resistance control inhibition approach an activation switch in the kinase mutations”, says Flynn. to kinases could have broader domain (which is encoded by exons In vivo, treatment of mice applicability. “We have extended this 17 and 18 in KIT and exons 18 and 19 carrying mutant KIT GIST cell line proprietary kinase switch control in PDGFRA). Phosphorylation of one xenografts with two doses of 25 and inhibitor platform to develop highly or more switch amino acids changes 100 mg/kg/day of ripretinib resulted selective, potent small-molecule drug the conformation from type I (active) in significant tumour regression. candidates that have the potential to type II (inactive) and vice versa, At the high dose, out of 10 mice, Furthermore, to directly inhibit activation of turning the kinases ‘off’ and ‘on’. 6 showed complete and 4 partial saturation other kinases”, says Flynn. These Most mutations in GIST (found in tumour regression. Both doses were mutagenesis compounds include inhibitors of approximately 70% of the patients) well tolerated and although tumours angiopoietin-1 receptor TIE2 and are loss-of-function mutations in relapsed after the end of the dosing studies macrophage colony-stimulating the inhibitory switch, and lead to period, survival at day 68 was 100% revealed that factor 1 receptor (CSF1R), which a shift in conformation towards a for ripretinib-treated mice compared ripretinib are both implicated in tumour with 25% for vehicle-treated mice. progression. type I active form. However, a small was able to percentage of primary activating In an imatinib-resistant GIST M. Teresa Villanueva, Senior Editor, mutations and almost all secondary patient-derived xenograft model, withstand Nature Reviews Drug Discovery resistance mutations in GIST are repeated dosing of 50 mg/kg twice This article is modified from the original in emergence of Nat. Rev. Drug Discov. gain-of-function mutations in daily for 28 days resulted in tumour de novo KIT (https://doi.org/10.1038/d41573-019-00099-4). the activating switch that stabilize the regression and extended survival resistance ORIGINAL ARTICLE Smith, B. D. et al. Ripretinib active type I conformation and lead to (100% compared with 10% for (DCC-2618) is a switch control kinase inhibitor of an even more uncontrolled activation vehicle-treated mice at day 57). mutations a broad spectrum of oncogenic and drug-resistant of KIT, says Flynn. These mutations Finally, on the basis of the KIT and PDGFRA variants. Cancer Cell 35, 738–751 (2019) confer resistance to FDA-approved promising preclinical data the authors 370 | JULY 2019 | VOLUME 19 www.nature.com/nrc.