Initial testing (stage 1) of AZD6244 (ARRY-142886) by the pediatric preclinical testing program

E. Anders Kolb, Richard Gorlick, Peter J. Houghton, Christopher L. Morton, Geoffrey Neale, Stephen T. Keir, Hernan Carol, Richard Lock, Doris Phelps, Min H. Kang, C. Patrick Reynolds, John M. Maris, Catherine Billups, Malcolm A. Smith

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Background: AZD6244 (ARRY-142886) is a potent small molecule inhibitor of MEK1/2 that is in phase 2 clinical development. Procedures: AZD6244 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel (1 nM-10 μM). In vivo AZD6244 was tested at a dose of 100 mg/kg administered orally twice daily 5 days per week for 6 weeks. Subsequently, AZD6244 was evaluated against two juvenile pilocytic astrocytoma (JPA) xenografts using once and twice daily dosing schedules. Phosphorylation of ERK1/2 was used as a surrogate for in vivo inhibition of MEK1/2 was determined by immunoblotting. Results: At the highest concentration used in vitro (10 μM) AZD6244 only inhibited growth by 50% in 5 of the 23 cell lines. Against the in vivo tumor panels, AZD6244 induced significant differences in EFS distribution in 10 of 37 (27%) solid tumor models and 0 of 6 acute lymphoblastic leukemia (ALL) models. There were no objective responses. Pharmacodynamic studies indicated at this dose and schedule AZD6244 completely inhibited ERK1/2 phosphorylation. AZD6244 was evaluated against two JPA xenografts, BT-35 (wild-type BRAF) and BT-40 (mutant [V600E] BRAF). BT-40 xenografts were highly sensitive to AZD6244, whereas BT-35 xenografts progressed on AZD6244 treatment. Conclusions: At the dose and schedule of administration used, AZD6244 as a single agent had limited in vitro and in vivo activity against the PPTP tumor panels despite inhibition of MEK1/2 activity. However, AZD6244 was highly active against BT-40 JPA xenografts that harbor constitutively activated BRAF, causing complete regressions. Pediatr Blood Cancer.

Original languageEnglish (US)
Pages (from-to)668-677
Number of pages10
JournalPediatric Blood and Cancer
Volume55
Issue number4
DOIs
StatePublished - Oct 2010

Keywords

  • AZD6244
  • Developmental therapeutics
  • Preclinical testing

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

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    Kolb, E. A., Gorlick, R., Houghton, P. J., Morton, C. L., Neale, G., Keir, S. T., Carol, H., Lock, R., Phelps, D., Kang, M. H., Reynolds, C. P., Maris, J. M., Billups, C., & Smith, M. A. (2010). Initial testing (stage 1) of AZD6244 (ARRY-142886) by the pediatric preclinical testing program. Pediatric Blood and Cancer, 55(4), 668-677. https://doi.org/10.1002/pbc.22576