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

Biomark Res. 2017 May 11:5:17. doi: 10.1186/s40364-017-0098-3. eCollection 2017.

Authors

Gulietta M Pupo^{1

2}, Suzanah C Boyd^{3

2}, Carina Fung^{3

2}, Matteo S Carlino^{1

2

4}, Alexander M Menzies^{2

5}, Bernadette Pedersen^{1

2}, Peter Johansson⁶, Nicholas K Hayward⁶, Richard F Kefford^{1

3

2

5}, Richard A Scolyer^{2

7

8}, Georgina V Long^{2

5}, Helen Rizos^{3

2}

Affiliations

¹ Centre for Cancer Research, The Westmead Millennium Institute for Medical Research, University of Sydney, Westmead Hospital, Westmead, NSW Australia.
² Melanoma Institute Australia, Sydney, NSW Australia.
³ Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW Australia.
⁴ Departments of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, NSW Australia.
⁵ Disciplines of Medicine, Sydney Medical School, The University of Sydney, Sydney, NSW Australia.
⁶ Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD Australia.
⁷ Disciplines of Pathology, Sydney Medical School, The University of Sydney, Sydney, NSW Australia.
⁸ Departments of Tissue Pathology and Diagnostic Oncology Royal Prince Alfred Hospital, Camperdown, NSW Australia.

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.

Keywords: BRAF inhibitor; BRAF splicing; Dabrafenib; Melanoma; Resistance.