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 mutantmelanomas and second-line treatment for patients who develop resistance.

Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma / Girotti, Maria Romina; Lopes, Filipa; Preece, Natasha; Niculescu Duvaz, Dan; Zambon, Alfonso; Davies, Lawrence; Whittaker, Steven; Saturno, Grazia; Viros, Amaya; Pedersen, Malin; Suijkerbuijk, Bart M. J. M.; Menard, Delphine; Mcleary, Robert; Johnson, Louise; Fish, Laura; Ejiama, Sarah; Sanchez Laorden, Berta; Hohloch, Juliane; Carragher, Neil; Macleod, Kenneth; Ashton, Garry; Marusiak, Anna A.; Fusi, Alberto; Brognard, John; Frame, Margaret; Lorigan, Paul; Marais, Richard; Springer, Caroline. - In: CANCER CELL. - ISSN 1535-6108. - 27:1(2015), pp. 85-96. [10.1016/j.ccell.2014.11.006]

Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma

ZAMBON, Alfonso;
2015

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 mutantmelanomas and second-line treatment for patients who develop resistance.
2015
11-dic-2014
27
1
85
96
Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma / Girotti, Maria Romina; Lopes, Filipa; Preece, Natasha; Niculescu Duvaz, Dan; Zambon, Alfonso; Davies, Lawrence; Whittaker, Steven; Saturno, Grazia; Viros, Amaya; Pedersen, Malin; Suijkerbuijk, Bart M. J. M.; Menard, Delphine; Mcleary, Robert; Johnson, Louise; Fish, Laura; Ejiama, Sarah; Sanchez Laorden, Berta; Hohloch, Juliane; Carragher, Neil; Macleod, Kenneth; Ashton, Garry; Marusiak, Anna A.; Fusi, Alberto; Brognard, John; Frame, Margaret; Lorigan, Paul; Marais, Richard; Springer, Caroline. - In: CANCER CELL. - ISSN 1535-6108. - 27:1(2015), pp. 85-96. [10.1016/j.ccell.2014.11.006]
Girotti, Maria Romina; Lopes, Filipa; Preece, Natasha; Niculescu Duvaz, Dan; Zambon, Alfonso; Davies, Lawrence; Whittaker, Steven; Saturno, Grazia; Vi...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1138859
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