Clinical significance of intronic variants in BRAF inhibitor resistant melanomas with altered BRAF transcript splicing

Gulietta M. Pupo; Suzanah C. Boyd; Carina Fung; Matteo S. Carlino; Alexander M. Menzies; Bernadette Pedersen; Peter Johansson; Nicholas K. Hayward; Richard F. Kefford; Richard A. Scolyer; Georgina V. Long; Helen Rizos

doi:10.1186/s40364-017-0098-3

Clinical significance of intronic variants in BRAF inhibitor resistant melanomas with altered BRAF transcript splicing

Gulietta M. Pupo, Suzanah C. Boyd, Carina Fung, Matteo S. Carlino, Alexander M. Menzies, Bernadette Pedersen, Peter Johansson, Nicholas K. Hayward, Richard F. Kefford, Richard A. Scolyer, Georgina V. Long, Helen Rizos^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Alternate BRAF splicing is the most common mechanism of acquired resistance to BRAF inhibitor treatment in melanoma. Recently, alternate BRAF exon 4-8 splicing was shown to involve an intronic mutation, located 51 nucleotides upstream of BRAF exon 9 within a predicted splicing branch point. This intronic mutation was identified in a single cell line but has not been examined in vivo. Herein we demonstrate that in three melanomas biopsied from patients with acquired resistance to BRAF inhibitors, alternate BRAF exon 4-8 splicing is not associated with this intronic branch point mutation. We also confirm that melanoma cells expressing BRAF splicing variants retain exquisite sensitivity to existing FDA-approved MEK inhibitors.

Original language	English
Article number	17
Pages (from-to)	1-4
Number of pages	4
Journal	Biomarker Research
Volume	5
Issue number	1
DOIs	https://doi.org/10.1186/s40364-017-0098-3
Publication status	Published - 11 May 2017

Bibliographical note

Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

Melanoma
BRAF inhibitor
BRAF splicing
Dabrafenib
Resistance

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10.1186/s40364-017-0098-3

Publisher version (open access)Final published version, 740 KBLicence: CC BY

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Pupo, G. M., Boyd, S. C., Fung, C., Carlino, M. S., Menzies, A. M., Pedersen, B., Johansson, P., Hayward, N. K., Kefford, R. F., Scolyer, R. A., Long, G. V., & Rizos, H. (2017). Clinical significance of intronic variants in BRAF inhibitor resistant melanomas with altered BRAF transcript splicing. Biomarker Research, 5(1), 1-4. Article 17. https://doi.org/10.1186/s40364-017-0098-3

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abstract = "Alternate BRAF splicing is the most common mechanism of acquired resistance to BRAF inhibitor treatment in melanoma. Recently, alternate BRAF exon 4-8 splicing was shown to involve an intronic mutation, located 51 nucleotides upstream of BRAF exon 9 within a predicted splicing branch point. This intronic mutation was identified in a single cell line but has not been examined in vivo. Herein we demonstrate that in three melanomas biopsied from patients with acquired resistance to BRAF inhibitors, alternate BRAF exon 4-8 splicing is not associated with this intronic branch point mutation. We also confirm that melanoma cells expressing BRAF splicing variants retain exquisite sensitivity to existing FDA-approved MEK inhibitors.",

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AU - Menzies, Alexander M.

AU - Pedersen, Bernadette

AU - Johansson, Peter

AU - Hayward, Nicholas K.

AU - Kefford, Richard F.

AU - Scolyer, Richard A.

AU - Long, Georgina V.

AU - Rizos, Helen

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N2 - Alternate BRAF splicing is the most common mechanism of acquired resistance to BRAF inhibitor treatment in melanoma. Recently, alternate BRAF exon 4-8 splicing was shown to involve an intronic mutation, located 51 nucleotides upstream of BRAF exon 9 within a predicted splicing branch point. This intronic mutation was identified in a single cell line but has not been examined in vivo. Herein we demonstrate that in three melanomas biopsied from patients with acquired resistance to BRAF inhibitors, alternate BRAF exon 4-8 splicing is not associated with this intronic branch point mutation. We also confirm that melanoma cells expressing BRAF splicing variants retain exquisite sensitivity to existing FDA-approved MEK inhibitors.

AB - Alternate BRAF splicing is the most common mechanism of acquired resistance to BRAF inhibitor treatment in melanoma. Recently, alternate BRAF exon 4-8 splicing was shown to involve an intronic mutation, located 51 nucleotides upstream of BRAF exon 9 within a predicted splicing branch point. This intronic mutation was identified in a single cell line but has not been examined in vivo. Herein we demonstrate that in three melanomas biopsied from patients with acquired resistance to BRAF inhibitors, alternate BRAF exon 4-8 splicing is not associated with this intronic branch point mutation. We also confirm that melanoma cells expressing BRAF splicing variants retain exquisite sensitivity to existing FDA-approved MEK inhibitors.

KW - Melanoma

KW - BRAF inhibitor

KW - BRAF splicing

KW - Dabrafenib

KW - Resistance

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Clinical significance of intronic variants in BRAF inhibitor resistant melanomas with altered BRAF transcript splicing

Abstract

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