Inhibition of MEK confers hypersensitivity to X-radiation in the context of BRAF mutation in a model of childhood astrocytoma.

Abstract

PURPOSE:

Curative therapy for childhood glioma presents challenges when complete resection is not possible. Patients with recurrent low-grade tumors or anaplastic astrocytoma may receive radiation treatment; however, the long-term sequellae from radiation treatment can be severe. As many childhood gliomas are associated with activation of BRAF, we have explored the combination of ionizing radiation with MEK inhibition in a model of BRAF-mutant anaplastic astrocytoma.

EXPERIMENTAL DESIGN:

The regulation of TORC1 signaling by BRAF was examined in BT-40 (BRAF mutant) and BT-35 (BRAF wild type) xenografts, in a cell line derived from the BT-40 xenograft and two adult BRAF mutant glioblastoma cell lines. The effect of MEK inhibition (selumetinib), XRT (total dose 10 Gy as 2 Gy daily fractions), or the combination of selumetinib and XRT was evaluated in subcutaneous BT-40 xenografts.

RESULTS:

Inhibition of MEK signaling by selumetinib suppressed TORC1 signaling only in the context of the BRAF-mutant both in vitro and in vivo. Inhibition of MEK signaling in BT-40 cells or in xenografts lead to a complete suppression of FANCD2 and conferred hypersensitivity to XRT in BT-40 xenografts without increasing local skin toxicity.

CONCLUSIONS:

Selumetinib suppressed TORC1 signaling in the context of BRAF mutation. Selumetinib caused a rapid downregulation of FANCD2 and markedly potentiated the effect of XRT. These data suggest the possibility of potentiating the effect of XRT selectively in tumor cells by MEK inhibition in the context of mutant BRAF or maintaining tumor control at lower doses of XRT that would decrease long-term sequelae.

• Authors: Adam Studebaker, Kathryn Bondra, Star Seum, Changxian Shen, Doris A Phelps, Christopher Chronowski, Justin Leasure, Paul D Smith, Raushan T Kurmasheva, Xiaokui Mo, Maryam Fouladi, Peter J Houghton
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 62 Issue 10 Pg. 1768-74 (Oct 2015) ISSN: 1545-5017 [Electronic] United States
• PMID: 25981859 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 Wiley Periodicals, Inc.

Chemical References

• AZD 6244
• Benzimidazoles
• Multiprotein Complexes
• BRAF protein, human
• Mechanistic Target of Rapamycin Complex 1
• Proto-Oncogene Proteins B-raf
• TOR Serine-Threonine Kinases
• MAP Kinase Kinase Kinases

Topics

• Animals
• Astrocytoma (genetics, radiotherapy)
• Benzimidazoles (adverse effects)
• Blotting, Western
• Cell Line, Tumor
• Female
• Humans
• MAP Kinase Kinase Kinases (antagonists & inhibitors)
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Mice, SCID
• Multiprotein Complexes (metabolism)
• Mutation
• Neoplasms, Experimental (genetics, radiotherapy)
• Proto-Oncogene Proteins B-raf (genetics)
• Radiotherapy (adverse effects)
• TOR Serine-Threonine Kinases (metabolism)
• Xenograft Model Antitumor Assays