Figure 1.
Sensitivity to trametinib of BRAFV600E mutant pediatric brain tumor PDX models correlates with suppression of MAPK and TORC1 signaling. A to C, sensitivity of BT-40, NCH-MN-1, and IC-3635 brain tumor PDX models to trametinib (1 mg/kg daily × 42 days). D to E, Pharmacodynamic changes in MAPK and TORC1 signaling following trametinib (1 mg/kg) administered on day 1 or treatment for 5 consecutive days. Tumors were harvested 4 hours after the final drug administration. F, Mice bearing BT-40, NCH-MN-1, or IC-3635 xenografts were untreated or received trametinib (1 mg/kg/day) for 5 days, and phosphorylation of TSC2 at an Akt site (T1462) and an MAPK site (S664) was determined. No phosphorylation of TSC2 at T1462 was detected in control or treated xenografts, whereas phosphorylation of TSC2 (S664) was decreased in trametinib-treated tumors. Trametinib induces phosphorylation of TSC2(T1462) in DBTRG cells, and expression of Myr-AKT3 induces phosphorylation of TSC2(T1462) in AM38C adult glioblastoma cells. G, Schema of MEKi sensitivity in cells with MAPK mediated inactivation of TSC2 without PI3K/Akt phosphorylation of TSC2. h, hours.