Abstract 5498: SHP2 inhibition enhances antitumor effect of mirdametinib in a pediatric brain tumor model bearing CDC42SE2BRAF fusion by rewiring the proteome and phosphoproteome landscape

Pediatric gliomas are the most common type of pediatric brain tumors representing wide range of molecularly and clinically heterogenous subtypes. The hyperactivity of mitogen-activated protein kinases (MAPK) pathway has been identified in the majority of pediatric glioma suggesting its therapeutic potential. However, pharmacologic targeting single MAPK pathway’s component is limited due to the development of drug resistance and differential response associated with tumor molecular landscape. Therefore, effective combination strategy in the framework of precision medicine is needed. Here we report combination benefit and molecular underpinning therapeutic response of brain penetrant MEK inhibitor (mirdametinib) and SHP2 inhibitor (SHP099) in a pediatric patient derived xenograft (PDX) and xenoline developed at our institution. Our model was derived from a pediatric patient who was diagnosed with rare high-grade subtype of glioma, anaplastic pleomorphic xanthoastrocytoma, and did not respond to MEK inhibitor, trametinib. Integrative multi-omics revealed molecular fidelity between our model and its patient tumor counterpart including the presence of 7q35 fusion, CDC52SE2-BRAF, CDKN2A/B loss, and MAPK pathway hyperactivation. In vitro studies using our xenoline IU-X128 demonstrated synergy between SHP099 and mirdametinib to curtail cell proliferation (p