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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Research Article

Dissecting Therapeutic Resistance to ERK Inhibition

Sharda Jha, Erick J. Morris, Alan Hruza, My Sam Mansueto, Gottfried Schroeder, Jaren Arbanas, Daniel McMasters, Clifford R Restaino, Priya Dayananth, Stuart Black, Nathaniel L Elsen, Anthony Mannarino, Alan Cooper, Stephen Fawell, Leigh Zawel, Lata Jayaraman and Ahmed A Samatar
Sharda Jha
Early Development and Discovery Sciences, Merck Research Laboratories
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Erick J. Morris
Early Development and Discovery Sciences, Merck Research Laboratories
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Alan Hruza
Structural Chemistry, Merck Research Laboratories
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My Sam Mansueto
Early Development and Discovery Sciences, Merck Research Laboratories
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Gottfried Schroeder
Early Development and Discovery Sciences, Merck Research Laboratories
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Jaren Arbanas
Early Development and Discovery Sciences, Merck Research Laboratories
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Daniel McMasters
Early Development and Disovery Sciences, Merck Research Laboratories
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Clifford R Restaino
Early Development and Discovery Sciences, Merck Research Laboratories
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Priya Dayananth
In vitro Pharmacology, Merck Research Laboratories
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Stuart Black
In vitro Pharmacology, Merck Research Institute
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Nathaniel L Elsen
Early Development and Discovery Sciences, Merck Research Laboratories
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Anthony Mannarino
Early Development and Discovery Sciences, Merck Research Laboratories
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Alan Cooper
In vitro Pharmacology, Merck Research Laboratories
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Stephen Fawell
Oncology Innovative Medicine Unit, AstraZeneca Pharmaceuticals LP
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Leigh Zawel
Boston Center for Therapeutic Innovation, Pfizer Inc.
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Lata Jayaraman
Oncology, Cerulean Pharma
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Ahmed A Samatar
Tumor Biology, TheraMet Biosciences
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  • For correspondence: ahmed.samatar@therametbio.com
DOI: 10.1158/1535-7163.MCT-15-0172
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Abstract

The MAPK pathway is frequently activated in many human cancers, particularly melanomas. A single nucleotide mutation in BRAF resulting in the substitution of glutamic acid for valine (V600E) causes constitutive activation of the downstream MAPK pathway. Selective BRAF and MEK inhibitor therapies have demonstrated remarkable anti-tumor responses in BRAFV600E mutant melanoma patients. However, initial tumor shrinkage is transient and the vast majority of patients develop resistance. We previously reported that SCH772984, an ERK 1/2 inhibitor, effectively suppressed MAPK pathway signaling and cell proliferation in BRAF, MEK and concurrent BRAF/MEK inhibitor resistant tumor models. ERK inhibitors are currently being evaluated in clinical trials and in anticipation of the likelihood of clinical resistance, we sought to prospectively model acquired resistance to SCH772984. Our data show that long term exposure of cells to SCH772984 leads to acquired resistance, attributable to a mutation of glycine to aspartic acid (G186D) in the DFG motif of ERK1. Structural and biophysical studies demonstrated specific defects in SCH772984 binding to mutant ERK. Taken together, these studies describe the interaction of SCH772984 with ERK and identify a novel mechanism of ERK inhibitor resistance through mutation of a single residue within the DFG motif.

  • Received March 27, 2015.
  • Revision received December 7, 2015.
  • Accepted December 23, 2015.
  • Copyright © 2016, American Association for Cancer Research.
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Published OnlineFirst February 1, 2016
doi: 10.1158/1535-7163.MCT-15-0172

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Dissecting Therapeutic Resistance to ERK Inhibition
Sharda Jha, Erick J. Morris, Alan Hruza, My Sam Mansueto, Gottfried Schroeder, Jaren Arbanas, Daniel McMasters, Clifford R Restaino, Priya Dayananth, Stuart Black, Nathaniel L Elsen, Anthony Mannarino, Alan Cooper, Stephen Fawell, Leigh Zawel, Lata Jayaraman and Ahmed A Samatar
Mol Cancer Ther February 1 2016 DOI: 10.1158/1535-7163.MCT-15-0172

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Dissecting Therapeutic Resistance to ERK Inhibition
Sharda Jha, Erick J. Morris, Alan Hruza, My Sam Mansueto, Gottfried Schroeder, Jaren Arbanas, Daniel McMasters, Clifford R Restaino, Priya Dayananth, Stuart Black, Nathaniel L Elsen, Anthony Mannarino, Alan Cooper, Stephen Fawell, Leigh Zawel, Lata Jayaraman and Ahmed A Samatar
Mol Cancer Ther February 1 2016 DOI: 10.1158/1535-7163.MCT-15-0172
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Copyright 2016 by the American Association for Cancer Research.

Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

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