Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma.

Maria Romina Girotti; Filipa Lopes; Natasha Preece; Dan Niculescu-Duvaz; Alfonso Zambon; Lawrence Davies; Steven Whittaker; Grazia Saturno; Amaya Viros; Malin Pedersen; Bart M.J.M. Suijkerbuijk; Delphine Menard; Robert McLeary; Louise Johnson; Laura Fish; Sarah Ejiama; Berta Sanchez-Laorden; Juliane Hohloch; Neil Carragher; Kenneth Macleod; Garry Ashton; Anna A. Marusiak; Alberto Fusi; John Brognard; Margaret Frame; Paul Lorigan; Richard Marais; Caroline Springer

doi:10.1016/j.ccell.2014.11.006

Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma.

Maria Romina Girotti, Filipa Lopes, Natasha Preece, Dan Niculescu-Duvaz, Alfonso Zambon, Lawrence Davies, Steven Whittaker, Grazia Saturno, Amaya Viros, Malin Pedersen, Bart M.J.M. Suijkerbuijk, Delphine Menard, Robert McLeary, Louise Johnson, Laura Fish, Sarah Ejiama, Berta Sanchez-Laorden, Juliane Hohloch, Neil Carragher, Kenneth MacleodGarry Ashton, Anna A. Marusiak, Alberto Fusi, John Brognard, Margaret Frame, Paul Lorigan, Richard Marais, Caroline Springer

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

Abstract

BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance.

Original language	English
Pages (from-to)	85-96
Number of pages	12
Journal	Cancer Cell
Volume	27
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2014.11.006 https://doi.org/10.1016/j.ccell.2014.11.006
Publication status	Published - 12 Jan 2015

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Manchester Cancer Research Centre

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Girotti, MR., Lopes, F., Preece, N., Niculescu-Duvaz, D., Zambon, A., Davies, L., Whittaker, S., Saturno, G., Viros, A., Pedersen, M., Suijkerbuijk, BM. J. M., Menard, D., McLeary, R., Johnson, L., Fish, L., Ejiama, S., Sanchez-Laorden, B., Hohloch, J., Carragher, N., ... Springer, C. (2015). Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma. Cancer Cell, 27(1), 85-96. https://doi.org/10.1016/j.ccell.2014.11.006, https://doi.org/10.1016/j.ccell.2014.11.006

@article{d0d8f8805d3b4aa39289a27f601be5ef,

title = "Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma.",

abstract = "BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance.",

author = "Maria Romina Girotti and Filipa Lopes and Natasha Preece and Dan Niculescu-Duvaz and Alfonso Zambon and Lawrence Davies and Steven Whittaker and Grazia Saturno and Amaya Viros and Malin Pedersen and Bart M.J.M. Suijkerbuijk and Delphine Menard and Robert McLeary and Louise Johnson and Laura Fish and Sarah Ejiama and Berta Sanchez-Laorden and Juliane Hohloch and Neil Carragher and Kenneth Macleod and Garry Ashton and Anna A. Marusiak and Alberto Fusi and John Brognard and Margaret Frame and Paul Lorigan and Richard Marais and Caroline Springer",

note = "Open Access funded by Cancer Research UK",

year = "2015",

month = jan,

day = "12",

doi = "10.1016/j.ccell.2014.11.006",

language = "English",

volume = "27",

pages = "85--96",

journal = "Cancer Cell",

issn = "1535-6108",

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Girotti, MR, Lopes, F, Preece, N, Niculescu-Duvaz, D, Zambon, A, Davies, L, Whittaker, S, Saturno, G, Viros, A, Pedersen, M, Suijkerbuijk, BMJM, Menard, D, McLeary, R, Johnson, L, Fish, L, Ejiama, S, Sanchez-Laorden, B, Hohloch, J, Carragher, N, Macleod, K, Ashton, G, Marusiak, AA, Fusi, A, Brognard, J, Frame, M, Lorigan, P, Marais, R & Springer, C 2015, 'Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma.', Cancer Cell, vol. 27, no. 1, pp. 85-96. https://doi.org/10.1016/j.ccell.2014.11.006, https://doi.org/10.1016/j.ccell.2014.11.006

TY - JOUR

T1 - Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma.

AU - Girotti, Maria Romina

AU - Lopes, Filipa

AU - Preece, Natasha

AU - Niculescu-Duvaz, Dan

AU - Zambon, Alfonso

AU - Davies, Lawrence

AU - Whittaker, Steven

AU - Saturno, Grazia

AU - Viros, Amaya

AU - Pedersen, Malin

AU - Suijkerbuijk, Bart M.J.M.

AU - Menard, Delphine

AU - McLeary, Robert

AU - Johnson, Louise

AU - Fish, Laura

AU - Ejiama, Sarah

AU - Sanchez-Laorden, Berta

AU - Hohloch, Juliane

AU - Carragher, Neil

AU - Macleod, Kenneth

AU - Ashton, Garry

AU - Marusiak, Anna A.

AU - Fusi, Alberto

AU - Brognard, John

AU - Frame, Margaret

AU - Lorigan, Paul

AU - Marais, Richard

AU - Springer, Caroline

N1 - Open Access funded by Cancer Research UK

PY - 2015/1/12

Y1 - 2015/1/12

N2 - BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance.

AB - BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance.

UR - http://europepmc.org/abstract/med/25500121

U2 - 10.1016/j.ccell.2014.11.006

DO - 10.1016/j.ccell.2014.11.006

M3 - Article

C2 - 25500121

SN - 1535-6108

VL - 27

SP - 85

EP - 96

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma.

Abstract

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UN SDGs

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