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Therapeutics, Targets, and Chemical Biology

Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models

Catherine A. Eberlein, Daniel Stetson, Aleksandra A. Markovets, Katherine J. Al-Kadhimi, Zhongwu Lai, Paul R. Fisher, Catherine B. Meador, Paula Spitzler, Eiki Ichihara, Sarah J. Ross, Miika J. Ahdesmaki, Ambar Ahmed, Laura E. Ratcliffe, Elizabeth L. Christey O'Brien, Claire H. Barnes, Henry Brown, Paul D. Smith, Jonathan R. Dry, Garry Beran, Kenneth S. Thress, Brian Dougherty, William Pao and Darren A.E. Cross
Catherine A. Eberlein
1AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
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Daniel Stetson
2AstraZeneca Oncology Innovative Medicines, Gatehouse Park, Waltham, Massachusetts.
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Aleksandra A. Markovets
2AstraZeneca Oncology Innovative Medicines, Gatehouse Park, Waltham, Massachusetts.
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Katherine J. Al-Kadhimi
1AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
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Zhongwu Lai
2AstraZeneca Oncology Innovative Medicines, Gatehouse Park, Waltham, Massachusetts.
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Paul R. Fisher
3AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
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Catherine B. Meador
4Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
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Paula Spitzler
4Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
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Eiki Ichihara
4Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
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Sarah J. Ross
1AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
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Miika J. Ahdesmaki
1AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
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Ambar Ahmed
2AstraZeneca Oncology Innovative Medicines, Gatehouse Park, Waltham, Massachusetts.
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Laura E. Ratcliffe
3AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
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Elizabeth L. Christey O'Brien
3AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom.
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Claire H. Barnes
1AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
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Henry Brown
1AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
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Paul D. Smith
1AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
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Jonathan R. Dry
2AstraZeneca Oncology Innovative Medicines, Gatehouse Park, Waltham, Massachusetts.
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Garry Beran
1AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
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Kenneth S. Thress
2AstraZeneca Oncology Innovative Medicines, Gatehouse Park, Waltham, Massachusetts.
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Brian Dougherty
2AstraZeneca Oncology Innovative Medicines, Gatehouse Park, Waltham, Massachusetts.
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William Pao
4Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.
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Darren A.E. Cross
1AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
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  • For correspondence: Darren.Cross@astrazeneca.com
DOI: 10.1158/0008-5472.CAN-14-3167 Published June 2015
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Abstract

Resistance to targeted EGFR inhibitors is likely to develop in EGFR-mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR-mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR tyrosine kinase inhibitors, including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002, or AZD9291. Compared with parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumors in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumors. Furthermore, these findings suggest that NRAS modifications in tumor samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition. Cancer Res; 75(12); 2489–500. ©2015 AACR.

Footnotes

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

  • Received October 30, 2014.
  • Revision received March 5, 2015.
  • Accepted March 17, 2015.
  • ©2015 American Association for Cancer Research.
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Cancer Research: 75 (12)
June 2015
Volume 75, Issue 12
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Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models
Catherine A. Eberlein, Daniel Stetson, Aleksandra A. Markovets, Katherine J. Al-Kadhimi, Zhongwu Lai, Paul R. Fisher, Catherine B. Meador, Paula Spitzler, Eiki Ichihara, Sarah J. Ross, Miika J. Ahdesmaki, Ambar Ahmed, Laura E. Ratcliffe, Elizabeth L. Christey O'Brien, Claire H. Barnes, Henry Brown, Paul D. Smith, Jonathan R. Dry, Garry Beran, Kenneth S. Thress, Brian Dougherty, William Pao and Darren A.E. Cross
Cancer Res June 15 2015 (75) (12) 2489-2500; DOI: 10.1158/0008-5472.CAN-14-3167

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Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models
Catherine A. Eberlein, Daniel Stetson, Aleksandra A. Markovets, Katherine J. Al-Kadhimi, Zhongwu Lai, Paul R. Fisher, Catherine B. Meador, Paula Spitzler, Eiki Ichihara, Sarah J. Ross, Miika J. Ahdesmaki, Ambar Ahmed, Laura E. Ratcliffe, Elizabeth L. Christey O'Brien, Claire H. Barnes, Henry Brown, Paul D. Smith, Jonathan R. Dry, Garry Beran, Kenneth S. Thress, Brian Dougherty, William Pao and Darren A.E. Cross
Cancer Res June 15 2015 (75) (12) 2489-2500; DOI: 10.1158/0008-5472.CAN-14-3167
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