EXTH-82. THE ROLE OF PTEN AND EPIGENETIC KINOME PROGRAMMING IN EGFR TKI RESPONSE IN GLIOBLASTOMA

Abstract

Abstract Glioblastoma (GBM) is the most common brain tumor and standard therapy only extends survival from 12 to 15 months. The receptor tyrosine kinase EGFR is altered in ~60% of GBM, resulting in aberrant activation of downstream pathways, including PI3K, that potentiate tumorigenesis. Though EGFR targeting has been successful in other cancers, clinical trials with EGFR tyrosine kinase inhibitors (TKI) have failed in GBM, in part due to resistance. Trial results suggested that the most common oncogenic EGFR variant, EGFRvIII (vIII), and negative regulator of PI3K signaling, PTEN, were biomarkers of response. To dissect the role of PTEN in GBM tumorigenesis and EGFR TKI response, we utilized vIII-expressing mouse astrocytes with and without functional Pten. Pten loss potentiated tumorigenesis in vitro and in vivo, as proliferation and stemness were significantly increased, and mouse survival was decreased upon implantation as orthoptic allografts. Both RNA-seq and proteomic analysis using multiplex inhibitor beads with mass spectrometry (MIB-MS) showed significantly altered kinome profiles. Pten deleted cells were 5-fold more sensitive to the EGFR TKI neratinib, a drug that induced Pten-dependent modulation of the kinase transcriptome over 48h. This acute transcriptional adaptation implies alteration of the epigenetic landscape. We hypothesized that disruption of enhancer dynamics via BET bromodomain inhibition would improve EGFR TKI durability. We found that cells expressing Pten were 10-fold more sensitive to multiple BET inhibitors, including JQ1, birabresib, and molibresib, and these inhibitors synergized with neratinib to reduce proliferation only in the Pten wild type model. Ongoing work is focused on defining the role of PTEN in maintenance of differential transcriptional and epigenetic programs. We will explore potential mechanistic roles of both the enzymatic and non-enzymatic functions of Pten and characterize its effect on hallmark cancer phenotypes such as proliferation, stemness/self-renewal, and tumorigenesis in the presence and absence of EGFR ± BET inhibitors.