Molecular analyses from a phase I trial of vemurafenib to study mechanism of action (MOA) and resistance in repeated biopsies from BRAF mutation–positive metastatic melanoma patients (pts)
| Autor: | Keith T. Flaherty, Olivia Spleiss, Astrid Koehler, J. A. Sosman, I. Puzanov, Rebecca Lee, K. B. Kim, A. Ribas, W. Wu, Kerstin Trunzer, Paul B. Chapman, Grant A. McArthur, Gideon Bollag, K. L. Nathanson |
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| Rok vydání: | 2011 |
| Předmět: | |
| Zdroj: | Journal of Clinical Oncology. 29:8502-8502 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2011.29.15_suppl.8502 |
| Popis: | 8502 Background: Vemurafenib (PLX4032), an oral, selective inhibitor of oncogenic V600E mutant BRAF, was evaluated for safety and pharmacokinetics in the Phase I dose escalation (DE) study PLX06-02 (Flaherty, et al. NEJM, 2010). Exploratory analyses included the investigation of MOA, pathway inhibition, and primary or acquired drug resistance from pts participating in the DE and melanoma extension phase. Methods: Biopsies were taken at baseline (BL), on vemurafenib therapy Day 15 (D15), and at progressive disease (PD). Protein expression (PTEN, Cyclin D1, p27, and Ki67), phosphorylation (pERK, pMEK and pAKT), apoptosis (TUNEL), gene sequence (MEK1), and mutations in oncogenes and tumour suppressor genes (404 mutations incl. BRAF, H-, K-, N-RAS, and PIK3CA using Sequenom MassArray) were analyzed. Results: Tumor tissue of 5 pts from the DE and 17 pts from the extension cohort was obtained (total samples: 18 BL, 12 D15, 20 PD). In 7/7 pts with paired BL/D15 samples, high levels of pERK were observed at BL fo... |
| Databáze: | OpenAIRE |
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