ATRT-12. BINIMETINIB SUPPRESSES THE GROWTH OF ATYPICAL TERATOID/RHABDOID TUMOR CELLS AND INDUCES APOPOTOSIS

Abstract

Atypical teratoid/rhabdoid (AT/RT) tumors are a class of malignant CNS tumors disproportionately affecting children with limited therapeutic options. Our group has previously demonstrated that the MAP kinase pathway is altered in a large proportion of these tumors and the MEK inhibitor selumetinib decreases cell growth and promotes apoptosis of AT/RT cells. One of the major drawbacks of selumetinib is its poor blood-brain barrier penetration. Binimetinib is a novel MEK inhibitor currently in pediatric phase II clinical trials for low grade glioma that has improved brain penetration. Binimetinib inhibits AT/RT growth at nanomolar concentrations, with IC25 values of 66.9 nM, 36.68 nM, 69.75 nM, 622.7 nM.and IC50 values of 101.06 nM, 107.69 nM, 691.485 nM and 1429.9 nM for CHLA266, CHLA06, BT37 and BT12 respectively. Binimetinib successfully decreases cell proliferation[ER1] and induces apoptosis (2–3 fold induction of cleaved PARP; p<0.005 for CHLA06 at 250 nM of MEK162 and at for BT37 at 1000 nM of MEK162 by cleaved caspase 3 positive cells on immunofluorescence) in AT/RT cell lines, suggesting binimetinib could offer a potential avenue for treating these deadly tumors.