DRES-03. EGFR-TARGETED THERAPY-INDUCED RESISTANCE MECHANISM IN MALIGNANT GLIOMAS

Epidermal growth factor receptor (EGFR) is frequently amplified, mutated and overexpressed in malignant gliomas. Our investigation of the proximal and distal responses to EGFR inhibition identified the molecular mechanisms for the therapeutic resistance of EGFR inhibition in gliomas. Oncogenic EGFRviii-dependent gliomas initially showed cytotoxic responses upon removal of oncogenic cue. However, during the initial regression, a subset of tumor cells with activated mesenchymal subtype gene expression program emerged by lineage reprogramming which promoted tumor relapse in the absence of EGFRviii signaling. This lineage switch is dependent on YAP1 activation as a response to therapy, and is a key to EGFRviii independent tumor growth. YAP signature stratifies overall survival of recurrent glioma patients. Inhibition of YAP1 activation suppressed mesenchymal gene expression and significantly delayed recurrence of gliomas. Our findings provide mechanisms underlying inefficacies of EGFR targeted therapy in glioblastoma and suggest a new combinatorial targeting of EGFR and YAP for deeper and more durable responses.