BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts

Kristel Kemper; Oscar Krijgsman; Xiangjun Kong; Paulien Cornelissen-Steijger; Aida Shahrabi; Fleur Weeber; Daphne L van der Velden; Onno B Bleijerveld; Thomas Kuilman; Roel J C Kluin; Chong Sun; Emile E Voest; Young Seok Ju; Ton N M Schumacher; A F Maarten Altelaar; Ultan McDermott; David J Adams; Christian U Blank; John B Haanen; Daniel S Peeper

doi:10.1016/j.celrep.2016.05.064

BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts

Kristel Kemper, Oscar Krijgsman, Xiangjun Kong, Paulien Cornelissen-Steijger, Aida Shahrabi, Fleur Weeber, Daphne L van der Velden, Onno B Bleijerveld, Thomas Kuilman, Roel J C Kluin, Chong Sun, Emile E Voest, Young Seok Ju, Ton N M Schumacher, A F Maarten Altelaar, Ultan McDermott, David J Adams, Christian U Blank, John B Haanen, Daniel S Peeper

Biomolecular Mass Spectrometry and Proteomics

NKI Protein Facility

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

Abstract

The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established a large collection of patient-derived xenografts (PDXs), derived from BRAF(V600E), NRAS(Q61), or BRAF(WT)/NRAS(WT) melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAF(V600E) protein harboring a kinase domain duplication (BRAF(V600E/DK)) in ∼10% of the cases, both in PDXs and in an independent patient cohort. While BRAF(V600E/DK) depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAF(V600E/DK)-expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients.

Original language	English
Pages (from-to)	263-277
Number of pages	15
Journal	Cell Reports [E]
Volume	16
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2016.05.064
Publication status	Published - 28 Jun 2016

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Kemper, K., Krijgsman, O., Kong, X., Cornelissen-Steijger, P., Shahrabi, A., Weeber, F., van der Velden, D. L., Bleijerveld, O. B., Kuilman, T., Kluin, R. J. C., Sun, C., Voest, E. E., Ju, Y. S., Schumacher, T. N. M., Altelaar, A. F. M., McDermott, U., Adams, D. J., Blank, C. U., Haanen, J. B., & Peeper, D. S. (2016). BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts. Cell Reports [E], 16(1), 263-277. https://doi.org/10.1016/j.celrep.2016.05.064

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title = "BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts",

abstract = "The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established a large collection of patient-derived xenografts (PDXs), derived from BRAF(V600E), NRAS(Q61), or BRAF(WT)/NRAS(WT) melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAF(V600E) protein harboring a kinase domain duplication (BRAF(V600E/DK)) in ∼10% of the cases, both in PDXs and in an independent patient cohort. While BRAF(V600E/DK) depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAF(V600E/DK)-expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients.",

author = "Kristel Kemper and Oscar Krijgsman and Xiangjun Kong and Paulien Cornelissen-Steijger and Aida Shahrabi and Fleur Weeber and {van der Velden}, {Daphne L} and Bleijerveld, {Onno B} and Thomas Kuilman and Kluin, {Roel J C} and Chong Sun and Voest, {Emile E} and Ju, {Young Seok} and Schumacher, {Ton N M} and Altelaar, {A F Maarten} and Ultan McDermott and Adams, {David J} and Blank, {Christian U} and Haanen, {John B} and Peeper, {Daniel S}",

year = "2016",

month = jun,

day = "28",

doi = "10.1016/j.celrep.2016.05.064",

language = "English",

volume = "16",

pages = "263--277",

journal = "Cell Reports [E]",

issn = "2211-1247",

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Kemper, K, Krijgsman, O, Kong, X, Cornelissen-Steijger, P, Shahrabi, A, Weeber, F, van der Velden, DL, Bleijerveld, OB, Kuilman, T, Kluin, RJC, Sun, C, Voest, EE, Ju, YS, Schumacher, TNM, Altelaar, AFM, McDermott, U, Adams, DJ, Blank, CU, Haanen, JB & Peeper, DS 2016, 'BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts', Cell Reports [E], vol. 16, no. 1, pp. 263-277. https://doi.org/10.1016/j.celrep.2016.05.064

TY - JOUR

T1 - BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts

AU - Kemper, Kristel

AU - Krijgsman, Oscar

AU - Kong, Xiangjun

AU - Cornelissen-Steijger, Paulien

AU - Shahrabi, Aida

AU - Weeber, Fleur

AU - van der Velden, Daphne L

AU - Bleijerveld, Onno B

AU - Kuilman, Thomas

AU - Kluin, Roel J C

AU - Sun, Chong

AU - Voest, Emile E

AU - Ju, Young Seok

AU - Schumacher, Ton N M

AU - Altelaar, A F Maarten

AU - McDermott, Ultan

AU - Adams, David J

AU - Blank, Christian U

AU - Haanen, John B

AU - Peeper, Daniel S

PY - 2016/6/28

Y1 - 2016/6/28

N2 - The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established a large collection of patient-derived xenografts (PDXs), derived from BRAF(V600E), NRAS(Q61), or BRAF(WT)/NRAS(WT) melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAF(V600E) protein harboring a kinase domain duplication (BRAF(V600E/DK)) in ∼10% of the cases, both in PDXs and in an independent patient cohort. While BRAF(V600E/DK) depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAF(V600E/DK)-expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients.

AB - The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established a large collection of patient-derived xenografts (PDXs), derived from BRAF(V600E), NRAS(Q61), or BRAF(WT)/NRAS(WT) melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAF(V600E) protein harboring a kinase domain duplication (BRAF(V600E/DK)) in ∼10% of the cases, both in PDXs and in an independent patient cohort. While BRAF(V600E/DK) depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAF(V600E/DK)-expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients.

U2 - 10.1016/j.celrep.2016.05.064

DO - 10.1016/j.celrep.2016.05.064

M3 - Article

C2 - 27320919

SN - 2211-1247

VL - 16

SP - 263

EP - 277

JO - Cell Reports [E]

JF - Cell Reports [E]

IS - 1

ER -

BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts

Abstract

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