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Ref Type Journal Article
PMID (34433654)
Authors Schreck KC, Morin A, Zhao G, Allen AN, Flannery P, Glantz M, Green AL, Jones C, Jones KL, Kilburn LB, Nazemi KJ, Samuel D, Sanford B, Solomon DA, Wang J, Pratilas CA, Nicolaides T, Mulcahy Levy JM
Title Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAFV600E-Mutant Human Glioma.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 27
Issue 22
Date 2021 Nov 15
URL
Abstract Text Selective RAF-targeted therapy is effective in some patients with BRAFV600E-mutated glioma, though emergent and adaptive resistance occurs through ill-defined mechanisms.Paired pre-/post- RAF inhibitor (RAFi)-treated glioma samples (N = 15) were obtained and queried for treatment-emergent genomic alterations using DNA and RNA sequencing (RNA-seq). Functional validation of putative resistance mechanisms was performed using established and patient-derived BRAFV600E-mutant glioma cell lines.Analysis of 15 tissue sample pairs identified 13 alterations conferring putative resistance were identified among nine paired samples (including mutations involving ERRFI1, BAP1, ANKHD1, and MAP2K1). We performed functional validation of mechanisms of resistance, including loss of NF1, PTEN, or CBL, in BRAFV600E-mutant glioma lines, and demonstrate they are capable of conferring resistance in vitro. Knockdown of CBL resulted in increased EGFR expression and phosphorylation, a possible mechanism for maintaining ERK signaling within the cell. Combination therapy with a MEKi or EGFR inhibitor was able to overcome resistance to BRAFi, in NF1 knockdown and CBL knockdown, respectively. Restoration of wild-type PTEN in B76 cells (PTEN-/-) restored sensitivity to BRAFi. We identified and validated CRAF upregulation as a mechanism of resistance in one resistant sample. RNA-seq analysis identified two emergent expression patterns in resistant samples, consistent with expression patterns of known glioma subtypes.Resistance mechanisms to BRAFi in glioma are varied and may predict effective precision combinations of targeted therapy, highlighting the importance of a personalized approach.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
TET2 V1199E missense unknown TET2 V1199E lies within the catalytic domain of the Tet2 protein (PMID: 24315485). V1199E has been demonstrated to confer RAF inhibitor resistance in the context of BRAF V600E (PMID: 34433654), but has not been biochemically characterized and therefore, its effect on Tet2 protein function is unknown (PubMed, Jun 2022). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E CBL dec exp high grade glioma predicted - resistant Neratinib Preclinical - Cell culture Actionable In a preclinical study, glioma cell lines harboring BRAF V600E and siRNA mediated knockdown of CBL were resistant to treatment with Nerlynx (neratinib) in culture (PMID: 34433654). 34433654
BRAF V600E CBL dec exp high grade glioma predicted - resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, siRNA mediated knockdown of CBL in glioma cell lines harboring BRAF V600E prevented Zelboraf (vemurafenib)-mediated inhibition of cell growth in culture (PMID: 34433654). 34433654
BRAF V600E high grade glioma predicted - sensitive LY3009120 Preclinical - Patient cell culture Actionable In a preclinical study, LY3009120 treatment led to inhibition of cell viability and growth in a patient-derived glioma cell line harboring BRAF V600E in culture (PMID: 34433654). 34433654
BRAF V600E TET2 V1199E high grade glioma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, a glioma cell line harboring BRAF V600E developed resistance after prolonged exposure to Zelboraf (vemurafenib) in culture, and was subsequently found to have acquired TET2 V1199E (PMID: 34433654). 34433654
BRAF V600E high grade glioma predicted - sensitive Belvarafenib Preclinical - Cell culture Actionable In a preclinical study, Belvarafenib (HM95573) treatment led to inhibition of cell viability in a patient-derived glioma cell line harboring BRAF V600E in culture (PMID: 34433654). 34433654
BRAF V600E high grade glioma no benefit ZM336372 Preclinical - Patient cell culture Actionable In a preclinical study, ZM336372 treatment did not lead to inhibition of cell growth in a patient-derived glioma cell line harboring BRAF V600E in culture (PMID: 34433654). 34433654
BRAF V600E high grade glioma sensitive LY3009120 + Vemurafenib Preclinical - Patient cell culture Actionable In a preclinical study, combination treatment with Zelboraf (vemurafenib) and LY3009120 treatment led to greater inhibition of cell growth compared to either agent alone in a patient-derived glioma cell line harboring BRAF V600E in culture (PMID: 34433654). 34433654
BRAF V600E high grade glioma predicted - sensitive Vemurafenib + ZM336372 Preclinical - Patient cell culture Actionable In a preclinical study, combination treatment with Zelboraf (vemurafenib) and ZM336372 treatment led to inhibition of cell growth in a patient-derived glioma cell line harboring BRAF V600E in culture (PMID: 34433654). 34433654
BRAF V600E CBL dec exp high grade glioma predicted - resistant Cobimetinib Preclinical - Cell culture Actionable In a preclinical study, glioma cell lines harboring BRAF V600E and siRNA mediated knockdown of CBL were resistant to treatment with Cotellic (cobimetinib) in culture (PMID: 34433654). 34433654