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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. | ||||||||||||
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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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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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, Nov 2024). | Y |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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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 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 | 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 | 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 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 | 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 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 | 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 |
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 |