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Experimental and Molecular Therapeutics

Abstract 4078: Tumors with class 3 BRAF mutants are sensitive to the inhibition of activated RAS

Zhan Yao, Rona Yaeger, Vanessa S. Rodrik-Outmezguine, Anthony Tao, Neilawattie M. Torres, Matthew T. Chang, Matthias Drosten, Huiyong Zhao, Fabiola Cecchi, Todd Hembrough, Judith Michels, Hervé Baumert, Linde Miles, Naomi M. Campbell, Elisa de Stanchina, David B. Solit, Mariano Barbacid, Barry S. Taylor and Neal Rosen
Zhan Yao
Mem. Sloan Kettering Cancer Ctr., New York, NY;
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Rona Yaeger
Mem. Sloan Kettering Cancer Ctr., New York, NY;
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Vanessa S. Rodrik-Outmezguine
Mem. Sloan Kettering Cancer Ctr., New York, NY;
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Anthony Tao
New York University, New York, NY;
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Neilawattie M. Torres
Mem. Sloan Kettering Cancer Ctr., New York, NY;
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Matthew T. Chang
Mem. Sloan Kettering Cancer Ctr., New York, NY;
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Matthias Drosten
Centro Nacional de Investigaciones Oncológicas, Madrid, Spain;
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Huiyong Zhao
Mem. Sloan Kettering Cancer Ctr., New York, NY;
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Fabiola Cecchi
NantOmics, LLC, Rockville, MD;
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Todd Hembrough
NantOmics, LLC, Rockville, MD;
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Judith Michels
Gustave Roussy Cancer Campus, Paris, France;
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Hervé Baumert
Saint Joseph Hospital, Paris, France.
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Linde Miles
Mem. Sloan Kettering Cancer Ctr., New York, NY;
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Naomi M. Campbell
Mem. Sloan Kettering Cancer Ctr., New York, NY;
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Elisa de Stanchina
Mem. Sloan Kettering Cancer Ctr., New York, NY;
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David B. Solit
Mem. Sloan Kettering Cancer Ctr., New York, NY;
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Mariano Barbacid
Centro Nacional de Investigaciones Oncológicas, Madrid, Spain;
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Barry S. Taylor
Mem. Sloan Kettering Cancer Ctr., New York, NY;
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Neal Rosen
Mem. Sloan Kettering Cancer Ctr., New York, NY;
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DOI: 10.1158/1538-7445.AM2017-4078 Published July 2017
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Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC

Abstract

Approximately two hundred mutant BRAF alleles have been identified in human tumors. Physiologic activation of RAF isoforms requires RAS-dependent induction of their dimerization. Activating BRAF mutants cause ERK dependent feedback inhibition of RAS.GTP and are RAS independent. As we have shown previously, they signal either as active monomers or RAS-independent constitutively active dimers. Here, we characterized a third class of BRAF mutants—those that have impaired kinase activity or are kinase dead. These class 3 BRAF mutants are sensitive to ERK-mediated feedback and they function in a RAS-dependent manner. In tumors, they bind more tightly to active RAS, thus enhancing their heterodimerization with CRAF. This is associated with the amplification of RAS-RAF-MEK-ERK signaling.

Since these mutants are sensitive to ERK-dependent feedback inhibition of RAS, their enhancement of ERK signaling in tumors requires concurrent dysregulation of RAS activation. Thus, melanomas with Class 3 mutations usually harbor coexistent RAS mutation or NF1 mutants/deletion, whereas receptor tyrosine kinase signaling is activated in lung and colorectal cancers with these mutants. Our model suggests that these tumors will be sensitive to the inhibition of RAS activation. Currently, no direct inhibitors of RAS activation are available. However, in support of this idea, inhibitors of activated RTK signaling in carcinomas with Class 3 BRAF mutants and wild type RAS is sufficient to markedly inhibit ERK signaling and their growth in in vivo murine models and in patients. We have thus defined a third subset of BRAF mutants, which is RAS-dependent. Tumors harboring such mutants are sensitive to tyrosine kinase inhibitors in tumors expressing wild type RAS and NF1.

Citation Format: Zhan Yao, Rona Yaeger, Vanessa S. Rodrik-Outmezguine, Anthony Tao, Neilawattie M. Torres, Matthew T. Chang, Matthias Drosten, Huiyong Zhao, Fabiola Cecchi, Todd Hembrough, Judith Michels, Hervé Baumert, Linde Miles, Naomi M. Campbell, Elisa de Stanchina, David B. Solit, Mariano Barbacid, Barry S. Taylor, Neal Rosen. Tumors with class 3 BRAF mutants are sensitive to the inhibition of activated RAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4078. doi:10.1158/1538-7445.AM2017-4078

  • ©2017 American Association for Cancer Research.
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Cancer Research: 77 (13 Supplement)
July 2017
Volume 77, Issue 13 Supplement
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Abstract 4078: Tumors with class 3 BRAF mutants are sensitive to the inhibition of activated RAS
Zhan Yao, Rona Yaeger, Vanessa S. Rodrik-Outmezguine, Anthony Tao, Neilawattie M. Torres, Matthew T. Chang, Matthias Drosten, Huiyong Zhao, Fabiola Cecchi, Todd Hembrough, Judith Michels, Hervé Baumert, Linde Miles, Naomi M. Campbell, Elisa de Stanchina, David B. Solit, Mariano Barbacid, Barry S. Taylor and Neal Rosen
Cancer Res July 1 2017 (77) (13 Supplement) 4078; DOI: 10.1158/1538-7445.AM2017-4078

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Abstract 4078: Tumors with class 3 BRAF mutants are sensitive to the inhibition of activated RAS
Zhan Yao, Rona Yaeger, Vanessa S. Rodrik-Outmezguine, Anthony Tao, Neilawattie M. Torres, Matthew T. Chang, Matthias Drosten, Huiyong Zhao, Fabiola Cecchi, Todd Hembrough, Judith Michels, Hervé Baumert, Linde Miles, Naomi M. Campbell, Elisa de Stanchina, David B. Solit, Mariano Barbacid, Barry S. Taylor and Neal Rosen
Cancer Res July 1 2017 (77) (13 Supplement) 4078; DOI: 10.1158/1538-7445.AM2017-4078
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