ID #824 Innovative precision-guided MAPK inhibition: expanding therapeutic benefits in pediatric glioma
Gabor Tax, Jie Mao, Roxanne Cadiz, Heike Peterziel, Jinhan Xie, Luke Fuller, David Lawrence, Mirae Bae, Alvin Lee, Jordan Roebuck, Lauren Brown, Jessica Harris, Karina Pazaky, Andrew Gifford, Dong-Anh Khuong-Quang, Ina Oehme, David Ziegler, Paul Ekert, Maria Tsoli, Ben Rayner, Emmy DolmanAbstract
Inhibitors of mitogen-activated protein kinase (MAPK) are among the most frequently recommended precision-guided therapies (PGTs) for pediatric brain tumors due to the high frequency of MAPK-activating gene alterations. However, acquired resistance to monotherapy remains a major challenge. Importantly, ex vivo tumor drug sensitivity profiling (DSP) has shown that MAPK inhibition can be effective in tumors lacking canonical MAPK alterations, suggesting that many more pediatric brain tumor patients may benefit from MAPK-targeting PGTs than previously recognized.
This study aims to fully understand which children with brain cancer are most likely to respond to MAPK-targeting PGTs and to identify the most effective and safe combination.
Ex vivo DSP was performed on 27 pediatric brain tumor samples from ZERO patients, including high-grade gliomas (HGGs) and diffuse midline gliomas (DMGs). Mitogen-activated protein kinase kinase (MEK; trametinib/pimasertib) or extracellular signal-regulated kinase (ERK; ulixertinib) inhibition was combined with rapidly accelerated fibrosarcoma (RAF; tovorafenib) or phosphatidylinositol 3-kinase (PI3K; paxalisib) inhibition to compare vertical MAPK versus horizontal MAPK/PI3K pathway blockade. Results were integrated with matched molecular profiling data.
Combined MEK and RAF inhibition (vertical MAPK blockade) produced robust synergy in 21 of 27 samples, with 16 achieving ≥80% cell killing at clinically relevant doses. Synergy occurred regardless of MAPK alterations. The combination prevented MAPK pathway reactivation observed with single-agent therapy in DMG cells. RNA sequencing revealed downregulation of MAPK targets, concurrent with dysregulated receptor tyrosine kinase signaling, and activated DNA damage response pathways. These data indicate that combined MEK and RAF inhibition disrupts feedback, resulting in replication stress or mitotic catastrophe.
This study demonstrates that dual MEK and RAF inhibition with clinically relevant, brain-penetrant agents is highly effective against HGG and DMG tumors, independent of MAPK status. Studies ascertaining relevant biomarkers within this setting are currently underway to guide enrollment of children into the OPTIMISE clinical trial.