Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	27	22	2021 Nov 15	6197-6208	Clin Cancer Res

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, Jan 2023).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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	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 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 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	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	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	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