Research Highlights

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

Original article Smith, B. D. et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants. Cancer Cell 37, 738–751 (2019) Credit: Amit Basu Photography/Moment Open/Getty Photography/Moment Basu Amit Credit:

Nature Reviews | Drug Discovery volume 18 | JULY 2019 | 499