Detailed imaging and genetic analysis reveal a secondary BRAF(L) (505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib

Marlous Hoogstraat; Christa G Gadellaa-van Hooijdonk; Inge Ubink; Nicolle J M Besselink; Mark Pieterse; Wouter Veldhuis; Marijn van Stralen; Eelco F J Meijer; Stefan M Willems; Michael A Hadders; Thomas Kuilman; Oscar Krijgsman; Daniel S Peeper; Marco J Koudijs; Edwin Cuppen; Emile E Voest; Martijn P Lolkema

doi:10.1111/pcmr.12347

Detailed imaging and genetic analysis reveal a secondary BRAF(L) (505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib

Marlous Hoogstraat, Christa G Gadellaa-van Hooijdonk, Inge Ubink, Nicolle J M Besselink, Mark Pieterse, Wouter Veldhuis, Marijn van Stralen, Eelco F J Meijer, Stefan M Willems, Michael A Hadders, Thomas Kuilman, Oscar Krijgsman, Daniel S Peeper, Marco J Koudijs, Edwin Cuppen, Emile E Voest, Martijn P Lolkema

Hubrecht Institute

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23 Citations (Scopus)

Abstract

Resistance to treatment is the main problem of targeted treatment for cancer. We followed ten patients during treatment with vemurafenib, by three-dimensional imaging. In all patients, only a subset of lesions progressed. Next-generation DNA sequencing was performed on sequential biopsies in four patients to uncover mechanisms of resistance. In two patients, we identified mutations that explained resistance to vemurafenib; one of these patients had a secondary BRAF L505H mutation. This is the first observation of a secondary BRAF mutation in a vemurafenib-resistant patient-derived melanoma sample, which confirms the potential importance of the BRAF L505H mutation in the development of therapy resistance. Moreover, this study hints toward an important role for tumor heterogeneity in determining the outcome of targeted treatments.

Original language	English
Pages (from-to)	318-23
Number of pages	6
Journal	Pigment Cell & Melanoma Research
Volume	28
Issue number	3
DOIs	https://doi.org/10.1111/pcmr.12347
Publication status	Published - May 2015

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Hoogstraat, M., Gadellaa-van Hooijdonk, C. G., Ubink, I., Besselink, N. J. M., Pieterse, M., Veldhuis, W., van Stralen, M., Meijer, E. F. J., Willems, S. M., Hadders, M. A., Kuilman, T., Krijgsman, O., Peeper, D. S., Koudijs, M. J., Cuppen, E., Voest, E. E., & Lolkema, M. P. (2015). Detailed imaging and genetic analysis reveal a secondary BRAF(L) (505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib. Pigment Cell & Melanoma Research, 28(3), 318-23. https://doi.org/10.1111/pcmr.12347

@article{8c6faa2a270346ebbdb3292eb37546dc,

title = "Detailed imaging and genetic analysis reveal a secondary BRAF(L) (505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib",

abstract = "Resistance to treatment is the main problem of targeted treatment for cancer. We followed ten patients during treatment with vemurafenib, by three-dimensional imaging. In all patients, only a subset of lesions progressed. Next-generation DNA sequencing was performed on sequential biopsies in four patients to uncover mechanisms of resistance. In two patients, we identified mutations that explained resistance to vemurafenib; one of these patients had a secondary BRAF L505H mutation. This is the first observation of a secondary BRAF mutation in a vemurafenib-resistant patient-derived melanoma sample, which confirms the potential importance of the BRAF L505H mutation in the development of therapy resistance. Moreover, this study hints toward an important role for tumor heterogeneity in determining the outcome of targeted treatments.",

author = "Marlous Hoogstraat and {Gadellaa-van Hooijdonk}, {Christa G} and Inge Ubink and Besselink, {Nicolle J M} and Mark Pieterse and Wouter Veldhuis and {van Stralen}, Marijn and Meijer, {Eelco F J} and Willems, {Stefan M} and Hadders, {Michael A} and Thomas Kuilman and Oscar Krijgsman and Peeper, {Daniel S} and Koudijs, {Marco J} and Edwin Cuppen and Voest, {Emile E} and Lolkema, {Martijn P}",

note = "{\textcopyright} 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.",

year = "2015",

month = may,

doi = "10.1111/pcmr.12347",

language = "English",

volume = "28",

pages = "318--23",

journal = "Pigment Cell & Melanoma Research",

issn = "1755-1471",

publisher = "Wiley-Blackwell",

number = "3",

}

Hoogstraat, M, Gadellaa-van Hooijdonk, CG, Ubink, I, Besselink, NJM, Pieterse, M, Veldhuis, W, van Stralen, M, Meijer, EFJ, Willems, SM, Hadders, MA, Kuilman, T, Krijgsman, O, Peeper, DS, Koudijs, MJ, Cuppen, E, Voest, EE & Lolkema, MP 2015, 'Detailed imaging and genetic analysis reveal a secondary BRAF(L) (505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib', Pigment Cell & Melanoma Research, vol. 28, no. 3, pp. 318-23. https://doi.org/10.1111/pcmr.12347

Detailed imaging and genetic analysis reveal a secondary BRAF(L) (505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib. / Hoogstraat, Marlous; Gadellaa-van Hooijdonk, Christa G; Ubink, Inge et al.
In: Pigment Cell & Melanoma Research, Vol. 28, No. 3, 05.2015, p. 318-23.

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

TY - JOUR

T1 - Detailed imaging and genetic analysis reveal a secondary BRAF(L) (505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib

AU - Hoogstraat, Marlous

AU - Gadellaa-van Hooijdonk, Christa G

AU - Ubink, Inge

AU - Besselink, Nicolle J M

AU - Pieterse, Mark

AU - Veldhuis, Wouter

AU - van Stralen, Marijn

AU - Meijer, Eelco F J

AU - Willems, Stefan M

AU - Hadders, Michael A

AU - Kuilman, Thomas

AU - Krijgsman, Oscar

AU - Peeper, Daniel S

AU - Koudijs, Marco J

AU - Cuppen, Edwin

AU - Voest, Emile E

AU - Lolkema, Martijn P

PY - 2015/5

Y1 - 2015/5

N2 - Resistance to treatment is the main problem of targeted treatment for cancer. We followed ten patients during treatment with vemurafenib, by three-dimensional imaging. In all patients, only a subset of lesions progressed. Next-generation DNA sequencing was performed on sequential biopsies in four patients to uncover mechanisms of resistance. In two patients, we identified mutations that explained resistance to vemurafenib; one of these patients had a secondary BRAF L505H mutation. This is the first observation of a secondary BRAF mutation in a vemurafenib-resistant patient-derived melanoma sample, which confirms the potential importance of the BRAF L505H mutation in the development of therapy resistance. Moreover, this study hints toward an important role for tumor heterogeneity in determining the outcome of targeted treatments.

AB - Resistance to treatment is the main problem of targeted treatment for cancer. We followed ten patients during treatment with vemurafenib, by three-dimensional imaging. In all patients, only a subset of lesions progressed. Next-generation DNA sequencing was performed on sequential biopsies in four patients to uncover mechanisms of resistance. In two patients, we identified mutations that explained resistance to vemurafenib; one of these patients had a secondary BRAF L505H mutation. This is the first observation of a secondary BRAF mutation in a vemurafenib-resistant patient-derived melanoma sample, which confirms the potential importance of the BRAF L505H mutation in the development of therapy resistance. Moreover, this study hints toward an important role for tumor heterogeneity in determining the outcome of targeted treatments.

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DO - 10.1111/pcmr.12347

M3 - Article

C2 - 25515853

SN - 1755-1471

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JO - Pigment Cell & Melanoma Research

JF - Pigment Cell & Melanoma Research

IS - 3

ER -

Hoogstraat M, Gadellaa-van Hooijdonk CG, Ubink I, Besselink NJM, Pieterse M, Veldhuis W et al. Detailed imaging and genetic analysis reveal a secondary BRAF(L) (505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib. Pigment Cell & Melanoma Research. 2015 May;28(3):318-23. doi: 10.1111/pcmr.12347

Detailed imaging and genetic analysis reveal a secondary BRAF(L) (505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib

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