Abstract
BI 882370 is a highly potent and selective RAF inhibitor that binds to the DFG-out (inactive) conformation of the BRAF kinase. The compound inhibited proliferation of human BRAF-mutant melanoma cells with 100× higher potency (1-10 nmol/L) than vemurafenib, whereas wild-type cells were not affected at 1,000 nmol/L. BI 882370 administered orally was efficacious in multiple mouse models of BRAF-mutant melanomas and colorectal carcinomas, and at 25 mg/kg twice daily showed superior efficacy compared with vemurafenib, dabrafenib, or trametinib (dosed to provide exposures reached in patients). To model drug resistance, A375 melanoma-bearing mice were initially treated with vemurafenib; all tumors responded with regression, but the majority subsequently resumed growth. Trametinib did not show any efficacy in this progressing population. BI 882370 induced tumor regression; however, resistance developed within 3 weeks. BI 882370 in combination with trametinib resulted in more pronounced regressions, and resistance was not observed during 5 weeks of second-line therapy. Importantly, mice treated with BI 882370 did not show any body weight loss or clinical signs of intolerability, and no pathologic changes were observed in several major organs investigated, including skin. Furthermore, a pilot study in rats (up to 60 mg/kg daily for 2 weeks) indicated lack of toxicity in terms of clinical chemistry, hematology, pathology, and toxicogenomics. Our results indicate the feasibility of developing novel compounds that provide an improved therapeutic window compared with first-generation BRAF inhibitors, resulting in more pronounced and long-lasting pathway suppression and thus improved efficacy.
Highlights
In multiple normal tissues, the MAPK signaling pathway transmits extracellular signals via tyrosine kinase receptors, RAS, RAF, MEK, and ERK proteins to regulate diverse cellular functions, including survival and proliferation
Complete responses are rarely observed, and median progression-free survival is less than one year even in patients treated with a RAF/MEK inhibitor combination [6], with biomarker studies indicating that the MAPK pathway is active in progressing tumors in spite of continuous treatment
It was shown that treatment of melanoma cells with BRAF inhibitors induces secretion of soluble factors that enhance the survival of drug-sensitive cells and accelerate the expansion of drug-resistant clones [36]
Summary
The MAPK signaling pathway transmits extracellular signals via tyrosine kinase receptors, RAS, RAF, MEK, and ERK proteins to regulate diverse cellular functions, including survival and proliferation. Hyperactivation of this pathway due to increased transducer expression (based on focal gene amplification) or higher intrinsic activity. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Prior presentation: The authors declare that some of the results were presented at the AACR meeting in 2013. Note added in proof: The crystal structure of the dabrafenib–BRAF kinase complex was recently published by Zhang and colleagues in ref. Note added in proof: The crystal structure of the dabrafenib–BRAF kinase complex was recently published by Zhang and colleagues in ref. 42
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