BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy

Douglas B. Johnson; Merrida A. Childress; Zachary R. Chalmers; Garrett M. Frampton; Siraj M. Ali; Samuel M. Rubinstein; David Fabrizio; Jeffrey S. Ross; Sohail Balasubramanian; Vincent A. Miller; Philip J. Stephens; Jeffrey A. Sosman; Christine M. Lovly

doi:10.1111/pcmr.12674

BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy

Douglas B. Johnson^*, Merrida A. Childress, Zachary R. Chalmers, Garrett M. Frampton, Siraj M. Ali, Samuel M. Rubinstein, David Fabrizio, Jeffrey S. Ross, Sohail Balasubramanian, Vincent A. Miller, Philip J. Stephens, Jeffrey A. Sosman, Christine M. Lovly

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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

31 Scopus citations

Abstract

BRAF and MEK inhibitors have improved clinical outcomes in advanced, BRAF^V ⁶⁰⁰-mutated melanomas. Acquired resistance occurs in most patients, with numerous and diverse drivers. We obtained pretreatment and progression biopsies from a patient who progressed on dabrafenib and trametinib. In addition to a preserved BRAF^V ^600E mutation, an internal deletion (rearrangement) of BRAF was observed in the progression sample. This deletion involved exons 2–8, which includes the Ras-binding domain, and is analogous to previously documented BRAF fusions and splice variants known to reactivate RAS-RAF-MEK-ERK signaling. In a large cohort of melanomas, 10 additional internal deletions were identified (0.4% of all melanomas; nine of which had concurrent BRAF mutations), as well as sporadically in other tumor types. Thus, we describe a novel mechanism of resistance to BRAF and MEK inhibition.

Original language	English (US)
Pages (from-to)	432-436
Number of pages	5
Journal	Pigment Cell and Melanoma Research
Volume	31
Issue number	3
DOIs	https://doi.org/10.1111/pcmr.12674
State	Published - May 2018

Funding

Funding information DBJ is supported by K23 CA204726 and by the James C. Bradford, Jr. Fund in Melanoma Cancer Research.

Keywords

BRAF
dabrafenib
internal deletion
rearrangement
resistance
trametinib
vemurafenib

ASJC Scopus subject areas

Oncology
General Biochemistry, Genetics and Molecular Biology
Dermatology

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10.1111/pcmr.12674

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Johnson, D. B., Childress, M. A., Chalmers, Z. R., Frampton, G. M., Ali, S. M., Rubinstein, S. M., Fabrizio, D., Ross, J. S., Balasubramanian, S., Miller, V. A., Stephens, P. J., Sosman, J. A., & Lovly, C. M. (2018). BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy. Pigment Cell and Melanoma Research, 31(3), 432-436. https://doi.org/10.1111/pcmr.12674

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title = "BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy",

abstract = "BRAF and MEK inhibitors have improved clinical outcomes in advanced, BRAFV 600-mutated melanomas. Acquired resistance occurs in most patients, with numerous and diverse drivers. We obtained pretreatment and progression biopsies from a patient who progressed on dabrafenib and trametinib. In addition to a preserved BRAFV 600E mutation, an internal deletion (rearrangement) of BRAF was observed in the progression sample. This deletion involved exons 2–8, which includes the Ras-binding domain, and is analogous to previously documented BRAF fusions and splice variants known to reactivate RAS-RAF-MEK-ERK signaling. In a large cohort of melanomas, 10 additional internal deletions were identified (0.4% of all melanomas; nine of which had concurrent BRAF mutations), as well as sporadically in other tumor types. Thus, we describe a novel mechanism of resistance to BRAF and MEK inhibition.",

keywords = "BRAF, dabrafenib, internal deletion, rearrangement, resistance, trametinib, vemurafenib",

author = "Johnson, {Douglas B.} and Childress, {Merrida A.} and Chalmers, {Zachary R.} and Frampton, {Garrett M.} and Ali, {Siraj M.} and Rubinstein, {Samuel M.} and David Fabrizio and Ross, {Jeffrey S.} and Sohail Balasubramanian and Miller, {Vincent A.} and Stephens, {Philip J.} and Sosman, {Jeffrey A.} and Lovly, {Christine M.}",

note = "Funding Information: Funding information DBJ is supported by K23 CA204726 and by the James C. Bradford, Jr. Fund in Melanoma Cancer Research. Publisher Copyright: {\textcopyright} 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd",

year = "2018",

month = may,

doi = "10.1111/pcmr.12674",

language = "English (US)",

volume = "31",

pages = "432--436",

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AU - Childress, Merrida A.

AU - Chalmers, Zachary R.

AU - Frampton, Garrett M.

AU - Ali, Siraj M.

AU - Rubinstein, Samuel M.

AU - Fabrizio, David

AU - Ross, Jeffrey S.

AU - Balasubramanian, Sohail

AU - Miller, Vincent A.

AU - Stephens, Philip J.

AU - Sosman, Jeffrey A.

AU - Lovly, Christine M.

N1 - Funding Information: Funding information DBJ is supported by K23 CA204726 and by the James C. Bradford, Jr. Fund in Melanoma Cancer Research. Publisher Copyright: © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

PY - 2018/5

Y1 - 2018/5

N2 - BRAF and MEK inhibitors have improved clinical outcomes in advanced, BRAFV 600-mutated melanomas. Acquired resistance occurs in most patients, with numerous and diverse drivers. We obtained pretreatment and progression biopsies from a patient who progressed on dabrafenib and trametinib. In addition to a preserved BRAFV 600E mutation, an internal deletion (rearrangement) of BRAF was observed in the progression sample. This deletion involved exons 2–8, which includes the Ras-binding domain, and is analogous to previously documented BRAF fusions and splice variants known to reactivate RAS-RAF-MEK-ERK signaling. In a large cohort of melanomas, 10 additional internal deletions were identified (0.4% of all melanomas; nine of which had concurrent BRAF mutations), as well as sporadically in other tumor types. Thus, we describe a novel mechanism of resistance to BRAF and MEK inhibition.

AB - BRAF and MEK inhibitors have improved clinical outcomes in advanced, BRAFV 600-mutated melanomas. Acquired resistance occurs in most patients, with numerous and diverse drivers. We obtained pretreatment and progression biopsies from a patient who progressed on dabrafenib and trametinib. In addition to a preserved BRAFV 600E mutation, an internal deletion (rearrangement) of BRAF was observed in the progression sample. This deletion involved exons 2–8, which includes the Ras-binding domain, and is analogous to previously documented BRAF fusions and splice variants known to reactivate RAS-RAF-MEK-ERK signaling. In a large cohort of melanomas, 10 additional internal deletions were identified (0.4% of all melanomas; nine of which had concurrent BRAF mutations), as well as sporadically in other tumor types. Thus, we describe a novel mechanism of resistance to BRAF and MEK inhibition.

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BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy

Abstract

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Keywords

ASJC Scopus subject areas

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