Tunable-Combinatorial Mechanisms of Acquired Resistance Limit the Efficacy of BRAF/MEK Cotargeting but Result in Melanoma Drug Addiction

Gatien Moriceau; Willy Hugo; Aayoung Hong; Hubing Shi; Xiangju Kong; Clarissa C. Yu; Richard C. Koya; Ahmed A. Samatar; Negar Khanlou; Jonathan Braun; Kathleen Ruchalski; Heike Seifert; James Larkin; Kimberly B. Dahlman; Douglas B. Johnson; Alain Algazi; Jeffrey A. Sosman; Antoni Ribas; Roger S. Lo

doi:10.1016/j.ccell.2014.11.018

Tunable-Combinatorial Mechanisms of Acquired Resistance Limit the Efficacy of BRAF/MEK Cotargeting but Result in Melanoma Drug Addiction

Gatien Moriceau, Willy Hugo, Aayoung Hong, Hubing Shi, Xiangju Kong, Clarissa C. Yu, Richard C. Koya, Ahmed A. Samatar, Negar Khanlou, Jonathan Braun, Kathleen Ruchalski, Heike Seifert, James Larkin, Kimberly B. Dahlman, Douglas B. Johnson, Alain Algazi, Jeffrey A. Sosman, Antoni Ribas, Roger S. Lo^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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

260 Scopus citations

Abstract

Combined BRAF- and MEK-targeted therapy improves upon BRAF inhibitor (BRAFi) therapy but is still beset by acquired resistance. We show that melanomas acquire resistance to combined BRAF and MEK inhibition by augmenting or combining mechanisms of single-agent BRAFi resistance. These double-drug resistance-associated genetic configurations significantly altered molecular interactions underlying MAPK pathway reactivation. ^V600EBRAF, expressed at supraphysiological levels because of ^V600EBRAF ultra-amplification, dimerized with and activated CRAF. In addition, MEK mutants enhanced interaction with overexpressed ^V600EBRAF via a regulatory interface at R662 of ^V600EBRAF. Importantly, melanoma cell lines selected for resistance to BRAFi+MEKi, but not those to BRAFi alone, displayed robust drug addiction, providing a potentially exploitable therapeutic opportunity.

Original language	English (US)
Pages (from-to)	240-256
Number of pages	17
Journal	Cancer cell
Volume	27
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2014.11.018
State	Published - Feb 9 2015

ASJC Scopus subject areas

Oncology
Cancer Research
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2014.11.018

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Moriceau, G., Hugo, W., Hong, A., Shi, H., Kong, X., Yu, C. C., Koya, R. C., Samatar, A. A., Khanlou, N., Braun, J., Ruchalski, K., Seifert, H., Larkin, J., Dahlman, K. B., Johnson, D. B., Algazi, A., Sosman, J. A., Ribas, A., & Lo, R. S. (2015). Tunable-Combinatorial Mechanisms of Acquired Resistance Limit the Efficacy of BRAF/MEK Cotargeting but Result in Melanoma Drug Addiction. Cancer cell, 27(2), 240-256. https://doi.org/10.1016/j.ccell.2014.11.018

@article{7727cb015b85405c9166a9254fd3c66f,

title = "Tunable-Combinatorial Mechanisms of Acquired Resistance Limit the Efficacy of BRAF/MEK Cotargeting but Result in Melanoma Drug Addiction",

abstract = "Combined BRAF- and MEK-targeted therapy improves upon BRAF inhibitor (BRAFi) therapy but is still beset by acquired resistance. We show that melanomas acquire resistance to combined BRAF and MEK inhibition by augmenting or combining mechanisms of single-agent BRAFi resistance. These double-drug resistance-associated genetic configurations significantly altered molecular interactions underlying MAPK pathway reactivation. V600EBRAF, expressed at supraphysiological levels because of V600EBRAF ultra-amplification, dimerized with and activated CRAF. In addition, MEK mutants enhanced interaction with overexpressed V600EBRAF via a regulatory interface at R662 of V600EBRAF. Importantly, melanoma cell lines selected for resistance to BRAFi+MEKi, but not those to BRAFi alone, displayed robust drug addiction, providing a potentially exploitable therapeutic opportunity.",

author = "Gatien Moriceau and Willy Hugo and Aayoung Hong and Hubing Shi and Xiangju Kong and Yu, {Clarissa C.} and Koya, {Richard C.} and Samatar, {Ahmed A.} and Negar Khanlou and Jonathan Braun and Kathleen Ruchalski and Heike Seifert and James Larkin and Dahlman, {Kimberly B.} and Johnson, {Douglas B.} and Alain Algazi and Sosman, {Jeffrey A.} and Antoni Ribas and Lo, {Roger S.}",

note = "Funding Information: We are grateful to G. Bollag (Plexxikon) for providing PLX4032; B. Chmielowski and J. Glaspy for coordinated patient care; Art Villanueva, Jackie Hernandez, Elizabeth Seja, and Christine Kivork for coordinating clinical trials and specimen collection; Donald Hucks for his technical assistance; and all patient volunteers. This work has been funded by Burroughs Wellcome Fund (to R.S.L.), Stand Up To Cancer (to R.S.L.), Melanoma Research Alliance (to R.S.L. and A.A.), the NIH (1R01CA176111 to R.S.L., 1P01CA168585 to A.R. and R.S.L., 5K24CA097588-09 to J.A.S.), the Ressler Family Foundation (to R.S.L. and A.R.), the Seaver institute (to R.S.L. and A.R.), the American Skin Association (to H. Shi and R.S.L.), the Harry J. Lloyd Charitable Trust (to R.S.L.), the Ian Copeland Melanoma Fund (to R.S.L.), the Steven C. Gordon Family Foundation (to R.S.L. and A.R.), the T. J. Martell Foundation (to K.B.D.), the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation (to K.B.D.), and the Royal Marsden (to J.L.). Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = feb,

day = "9",

doi = "10.1016/j.ccell.2014.11.018",

language = "English (US)",

volume = "27",

pages = "240--256",

journal = "Cancer cell",

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Moriceau, G, Hugo, W, Hong, A, Shi, H, Kong, X, Yu, CC, Koya, RC, Samatar, AA, Khanlou, N, Braun, J, Ruchalski, K, Seifert, H, Larkin, J, Dahlman, KB, Johnson, DB, Algazi, A, Sosman, JA, Ribas, A & Lo, RS 2015, 'Tunable-Combinatorial Mechanisms of Acquired Resistance Limit the Efficacy of BRAF/MEK Cotargeting but Result in Melanoma Drug Addiction', Cancer cell, vol. 27, no. 2, pp. 240-256. https://doi.org/10.1016/j.ccell.2014.11.018

TY - JOUR

T1 - Tunable-Combinatorial Mechanisms of Acquired Resistance Limit the Efficacy of BRAF/MEK Cotargeting but Result in Melanoma Drug Addiction

AU - Moriceau, Gatien

AU - Hugo, Willy

AU - Hong, Aayoung

AU - Shi, Hubing

AU - Kong, Xiangju

AU - Yu, Clarissa C.

AU - Koya, Richard C.

AU - Samatar, Ahmed A.

AU - Khanlou, Negar

AU - Braun, Jonathan

AU - Ruchalski, Kathleen

AU - Seifert, Heike

AU - Larkin, James

AU - Dahlman, Kimberly B.

AU - Johnson, Douglas B.

AU - Algazi, Alain

AU - Sosman, Jeffrey A.

AU - Ribas, Antoni

AU - Lo, Roger S.

N1 - Funding Information: We are grateful to G. Bollag (Plexxikon) for providing PLX4032; B. Chmielowski and J. Glaspy for coordinated patient care; Art Villanueva, Jackie Hernandez, Elizabeth Seja, and Christine Kivork for coordinating clinical trials and specimen collection; Donald Hucks for his technical assistance; and all patient volunteers. This work has been funded by Burroughs Wellcome Fund (to R.S.L.), Stand Up To Cancer (to R.S.L.), Melanoma Research Alliance (to R.S.L. and A.A.), the NIH (1R01CA176111 to R.S.L., 1P01CA168585 to A.R. and R.S.L., 5K24CA097588-09 to J.A.S.), the Ressler Family Foundation (to R.S.L. and A.R.), the Seaver institute (to R.S.L. and A.R.), the American Skin Association (to H. Shi and R.S.L.), the Harry J. Lloyd Charitable Trust (to R.S.L.), the Ian Copeland Melanoma Fund (to R.S.L.), the Steven C. Gordon Family Foundation (to R.S.L. and A.R.), the T. J. Martell Foundation (to K.B.D.), the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation (to K.B.D.), and the Royal Marsden (to J.L.). Publisher Copyright: © 2015 Elsevier Inc.

PY - 2015/2/9

Y1 - 2015/2/9

N2 - Combined BRAF- and MEK-targeted therapy improves upon BRAF inhibitor (BRAFi) therapy but is still beset by acquired resistance. We show that melanomas acquire resistance to combined BRAF and MEK inhibition by augmenting or combining mechanisms of single-agent BRAFi resistance. These double-drug resistance-associated genetic configurations significantly altered molecular interactions underlying MAPK pathway reactivation. V600EBRAF, expressed at supraphysiological levels because of V600EBRAF ultra-amplification, dimerized with and activated CRAF. In addition, MEK mutants enhanced interaction with overexpressed V600EBRAF via a regulatory interface at R662 of V600EBRAF. Importantly, melanoma cell lines selected for resistance to BRAFi+MEKi, but not those to BRAFi alone, displayed robust drug addiction, providing a potentially exploitable therapeutic opportunity.

AB - Combined BRAF- and MEK-targeted therapy improves upon BRAF inhibitor (BRAFi) therapy but is still beset by acquired resistance. We show that melanomas acquire resistance to combined BRAF and MEK inhibition by augmenting or combining mechanisms of single-agent BRAFi resistance. These double-drug resistance-associated genetic configurations significantly altered molecular interactions underlying MAPK pathway reactivation. V600EBRAF, expressed at supraphysiological levels because of V600EBRAF ultra-amplification, dimerized with and activated CRAF. In addition, MEK mutants enhanced interaction with overexpressed V600EBRAF via a regulatory interface at R662 of V600EBRAF. Importantly, melanoma cell lines selected for resistance to BRAFi+MEKi, but not those to BRAFi alone, displayed robust drug addiction, providing a potentially exploitable therapeutic opportunity.

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UR - http://www.scopus.com/inward/citedby.url?scp=84922875490&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2014.11.018

DO - 10.1016/j.ccell.2014.11.018

M3 - Article

C2 - 25600339

AN - SCOPUS:84922875490

SN - 1535-6108

VL - 27

SP - 240

EP - 256

JO - Cancer cell

JF - Cancer cell

IS - 2

ER -

Tunable-Combinatorial Mechanisms of Acquired Resistance Limit the Efficacy of BRAF/MEK Cotargeting but Result in Melanoma Drug Addiction

Abstract

ASJC Scopus subject areas

UN SDGs

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