TBIO-21. ANALYSIS OF PAIRED BRAFV600E MUTANT GLIOMA PATIENT SAMPLES IDENTIFIES NOVEL RESISTANCE MECHANISMS TO TARGETED BRAF INHIBITION

Abstract

BRAF^V600E mutations occur in a variety of gliomas and BRAF^V600E targeted therapies have provided new treatment options. Trials in melanoma and colorectal cancer, as well as early results in CNS tumors, indicate a high risk for the development of resistance. To date there is little data available for resistance mechanisms in glioma patients treated with BRAF^V600E inhibition. To identify molecular and pathway alterations driving resistance, we performed targeted next-generation DNA sequencing, RNA sequencing, and Ingenuity Pathway Analysis (IPA) on paired pre-treatment and post-resistance primary pediatric glioma samples (n=10) and cell lines (n=2). Unique genetic alterations likely driving tumor recurrence and resistance to BRAF inhibition were identified. Novel mutations in post-resistance samples included a de novo mutation in the CBL gene within the RING finger domain of the E3 ubiquitin ligase protein that has been recurrently found in myeloid neoplasms, a frameshift mutation in the RB1 tumor suppressor gene, and a nonsense mutation in ERRFI1, which encodes a negative regulator of EGFR signaling. IPA analysis demonstrated significant pathway activation differences in post-resistance samples. There was a predominance of upregulated receptor tyrosine kinase pathways including EGFR, NTRK2, TGFB1, estrogen receptor, ERBB2, and PI3K. Expected up-regulation of MEK, MAPK1, MAP2k1 and ERK1/2 pathways were found. The altered pathways were unique for each paired set. These data suggest that pediatric gliomas develop resistance to BRAF inhibition using a multitude of genetic and transcriptional mechanisms that are potentially distinct in each tumor, and with novel resistance mutations not found in resistant melanoma or colorectal cancers.

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