Dataset Information

Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAF^V600E-Mutant Human Glioma.

ABSTRACT:

Purpose

Selective RAF-targeted therapy is effective in some patients with BRAF^V600E-mutated glioma, though emergent and adaptive resistance occurs through ill-defined mechanisms.

Experimental design

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 BRAF^V600E-mutant glioma cell lines.

Results

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 BRAF^V600E-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.

Conclusions

Resistance mechanisms to BRAFi in glioma are varied and may predict effective precision combinations of targeted therapy, highlighting the importance of a personalized approach.

SUBMITTER: Schreck KC

PROVIDER: S-EPMC8595717 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAF<sup>V600E</sup>-Mutant Human Glioma.

Schreck Karisa C KC Morin Andrew A Zhao Guisheng G Allen Amy N AN Flannery Patrick P Glantz Michael M Green Adam L AL Jones Chris C Jones Kenneth L KL Kilburn Lindsay B LB Nazemi Kellie J KJ Samuel David D Sanford Bridget B Solomon David A DA Wang Jiawan J Pratilas Christine A CA Nicolaides Theodore T Mulcahy Levy Jean M JM

Clinical cancer research : an official journal of the American Association for Cancer Research 20210825 22

<h4>Purpose</h4>Selective RAF-targeted therapy is effective in some patients with BRAF<sup>V600E</sup>-mutated glioma, though emergent and adaptive resistance occurs through ill-defined mechanisms.<h4>Experimental design</h4>Paired pre-/post- RAF inhibitor (RAFi)-treated glioma samples (<i>N</i> = 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 ...[more]

PMID: 34433654

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Project description:BackgroundCombinatorial inhibition of epidermal growth factor receptor (EGFR) and BRAF shows remarkable clinical benefits in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC). However, the tumor may inevitably develop resistance to the targeted therapy, thereby limiting the response rate and durability. This study aimed to determine the genetic alterations associated with intrinsic and acquired resistance to EGFR/BRAF inhibitors in BRAF V600E-mutant mCRC.MethodsTargeted sequencing of 520 cancer-related genes was performed in tumor tissues and in plasma samples collected from patients with BRAF V600E-mutant mCRC, who were treated with EGFR/BRAF ± MEK inhibitors, before and after the targeted treatment. Clinical benefit was defined as an objective response or a stable disease lasting longer than the median progression-free survival (PFS).ResultsIn all, 25 patients with BRAF V600E-mutant mCRC were included in this study. Those with RNF43 mutations (n = 8) were more likely to achieve clinical benefit from EGFR/BRAF inhibitors than those with wild-type RNF43 (87.5% versus 37.5%, p = 0.034). Genetic alterations in receptor tyrosine kinase genes (n = 6) were associated with worse PFS (p = 0.005). Among the 23 patients whose disease progressed after the EGFR/BRAF-targeted therapy, at least one acquired resistance-related mutation was detected in 12 patients. Acquired mutations were most frequently observed in the mitogen-activated protein kinase pathway-related genes (n = 9), including KRAS (G12D and Q61H/R), NRAS (Q61L/R/K and amplification), BRAF (amplification), and MEK1 (K57T). MET amplification and PIK3R1 Q579fs mutation emerged in three patients and one patient, respectively, after disease progression.ConclusionMultiple genetic alterations are associated with clinical benefits and resistance to EGFR/BRAF inhibitors in BRAF V600E-mutant mCRC. Our findings provide novel insights into strategies for overcoming resistance to EGFR/BRAF inhibitors in patients with BRAF V600E-mutant mCRC.

Dataset Information

Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAF^V600E-Mutant Human Glioma.

Purpose

Experimental design

Results

Conclusions

Publications

Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAF<sup>V600E</sup>-Mutant Human Glioma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAFV600E-Mutant Human Glioma.

Purpose

Experimental design

Results

Conclusions

Publications

Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAF<sup>V600E</sup>-Mutant Human Glioma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAF^V600E-Mutant Human Glioma.