PTPS-30COMPARISON OF MAPK PATHWAY TARGETS AS POTENTIAL THERAPIES FOR MAPK-ACTIVATED GLIOMAS

Abstract

The RAS/RAF/MEK/MAPK signaling pathway plays a key role in regulating cell proliferation, survival and differentiation. As hyperactivation of MAPK signaling is a common driver in a subgroup of adult and pediatric gliomas, MAPK pathway blockade has been an attractive target for anti-glioma therapy. We have previously shown that pharmacological inhibition of BRAF and MEK significantly reduces glioma growth in intracranial xenograft models. Here, we compare the efficacy of inhibiting three MAPK pathway targets: BRAF (PLX4720 and PLX4032), MEK (PD901 and GDC0973) and ERK (SCH772984), in reducing glioma growth. In all of the three glioma cell lines examined, AM38 (BRAFV600E-mutant), DBTRG-05MG (BRAFV600E-mutant) and LN229 (NF-1 deficient), ERK and MEK inhibition efficiently suppressed the activation of downstream effectors of MAPK pathway, including p90RSK and cyclin D1, at less than 1uM. In contrast, BRAFV600E inhibitor PLX4720 and PLX4032 inhibits MEK and ERK phosphorylation at 0.1 uM, but yield insignificant effects on downstream components of MAPK (p90RSK and cyclin D1) even at high concentration (10 uM). Concordant with the extent of MAPK pathway blockade, MEK and ERK inhibition is more efficient in suppressing glioma cell growth compared to BRAF inhibition. Future work is required to understand the mechanisms underlying the variations in potency amongst inhibiting various MAPK pathway targets.