LAUSR

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<0.05). Moreover, this combination was well tolerated in our PDX, IU-RHT128, and potentiated anti-tumor effect of the single agent within clinically achievable doses. Reverse Phase Proteome Array (RPPA) identified MAPK reactivation via Mushasi RNA binding protein-PI3K-AKT crosstalk as a potential innate resistance mechanism to single agent MEK inhibitor in the PDX tumor. Further, tandem mass tags (TMT)-LC-MS/MS profiling on tumor treated with single agent SHP099 or mirdametinib and their combination revealed that combination therapy does not only revert certain proteome and phosphoproteome reprogramming from single agent treatment but also created a novel landscape which can be associated with anti-tumor effect. In this case, kinase network reprograming leading to MAPK reactivation was identified in mirdametinib treated tumor which was attenuated in the combination treatment. In summary, our results demonstrated that combination SHP099 and mirdametinib is superior to single agent alone in the pediatric A-PXA brain tumor model with proteome and phosphoproteome reprogramming of multiple networks as potential molecular mechanisms underlying therapeutic benefit of combination therapy. Ultimately, clinical translation of this finding will potentially benefit patient of this malignant rare pediatric glioma subset which currently does not have standard therapy. Citation Format: Nur P. Damayanti, Anthony Alfonso, Josue D. Ordaz, Erika Dobrota, M. Reza Saadatzadeh, Pankita Pandya, Barbara J. Bailey, Khadijeh Bijangi-Vishehsaraei, Harlan E. Shannon, Kathy Coy, Melissa Trowbridge, Anthony L. Sinn, Rosa Gallager, Julia Wulfkuhle, Emanuel Petricoin, Amber Mosley, Mark S. Marshall, Alex Lion, Michael J. Fergusson, Karl Balsara, Karen E. Pollok. SHP2 inhibition enhances antitumor effect of mirdametinib in a pediatric brain tumor model bearing CDC42SE2BRAF fusion by rewiring the proteome and phosphoproteome landscape. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5498.