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Molecular Cancer Research
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Oncogenes and Tumor Suppressors

Hyperactivation of MAPK Signaling Is Deleterious to RAS/RAF-mutant Melanoma

Grace P. Leung, Tianshu Feng, Frederic D. Sigoillot, Felipe C. Geyer, Matthew D. Shirley, David A. Ruddy, Daniel P. Rakiec, Alyson K. Freeman, Jeffrey A. Engelman, Mariela Jaskelioff and Darrin D. Stuart
Grace P. Leung
1Oncology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Tianshu Feng
1Oncology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Frederic D. Sigoillot
2Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Felipe C. Geyer
1Oncology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Matthew D. Shirley
1Oncology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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David A. Ruddy
1Oncology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Daniel P. Rakiec
1Oncology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Alyson K. Freeman
1Oncology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Jeffrey A. Engelman
1Oncology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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Mariela Jaskelioff
1Oncology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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  • For correspondence: darrin.stuart@novartis.com mariela.jaskelioff@novartis.com
Darrin D. Stuart
1Oncology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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  • For correspondence: darrin.stuart@novartis.com mariela.jaskelioff@novartis.com
DOI: 10.1158/1541-7786.MCR-18-0327
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Abstract

The most frequent genetic alterations in melanoma are gain-of-function (GOF) mutations in BRAF, which result in RAF–MEK–ERK signaling pathway addiction. Despite therapeutic success of RAF and MEK inhibitors in treating BRAFV600-mutant tumors, a major challenge is the inevitable emergence of drug resistance, which often involves reactivation of the MAPK pathway. Interestingly, resistant tumors are often sensitive to drug withdrawal, suggesting that hyperactivation of the MAPK pathway is not tolerated. To further characterize this phenomenon, isogenic models of inducible MAPK hyperactivation in BRAFV600E melanoma cells were generated by overexpression of ERK2. Using this model system, supraphysiologic levels of MAPK signaling led to cell death, which was reversed by MAPK inhibition. Furthermore, complete tumor regression was observed in an ERK2-overexpressing xenograft model. To identify mediators of MAPK hyperactivation–induced cell death, a large-scale pooled shRNA screen was conducted, which revealed that only shRNAs against BRAF and MAP2K1 rescued loss of cell viability. This suggested that no single downstream ERK2 effector was required, consistent with pleiotropic effects on multiple cellular stress pathways. Intriguingly, the detrimental effect of MAPK hyperactivation could be partially attributed to secreted factors, and more than 100 differentially secreted proteins were identified. The effect of ERK2 overexpression was highly context dependent, as RAS/RAF mutant but not RAS/RAF wild-type melanoma were sensitive to this perturbation.

Implications: This vulnerability to MAPK hyperactivation raises the possibility of novel therapeutic approaches for RAS/RAF-mutant cancers. Mol Cancer Res; 1–13. ©2018 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Received April 3, 2018.
  • Revision received July 25, 2018.
  • Accepted August 30, 2018.
  • Published first September 10, 2018.
  • ©2018 American Association for Cancer Research.
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This OnlineFirst version was published on October 26, 2018
doi: 10.1158/1541-7786.MCR-18-0327

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Hyperactivation of MAPK Signaling Is Deleterious to RAS/RAF-mutant Melanoma
Grace P. Leung, Tianshu Feng, Frederic D. Sigoillot, Felipe C. Geyer, Matthew D. Shirley, David A. Ruddy, Daniel P. Rakiec, Alyson K. Freeman, Jeffrey A. Engelman, Mariela Jaskelioff and Darrin D. Stuart
Mol Cancer Res October 26 2018 DOI: 10.1158/1541-7786.MCR-18-0327

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Hyperactivation of MAPK Signaling Is Deleterious to RAS/RAF-mutant Melanoma
Grace P. Leung, Tianshu Feng, Frederic D. Sigoillot, Felipe C. Geyer, Matthew D. Shirley, David A. Ruddy, Daniel P. Rakiec, Alyson K. Freeman, Jeffrey A. Engelman, Mariela Jaskelioff and Darrin D. Stuart
Mol Cancer Res October 26 2018 DOI: 10.1158/1541-7786.MCR-18-0327
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