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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Cancer Biology and Translational Studies

Distinct Transcriptional Programming Drive Response to MAPK Inhibition in BRAFV600-Mutant Melanoma Patient-Derived Xenografts

Tianshu Feng, Javad Golji, Ailing Li, Xiamei Zhang, David A. Ruddy, Daniel P. Rakiec, Felipe C. Geyer, Jane Gu, Hui Gao, Juliet A. Williams, Darrin D. Stuart and Matthew J. Meyer
Tianshu Feng
Oncology Drug Discovery, Novartis Institutes for BioMedical Research (NIBR), Cambridge, Massachusetts.
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Javad Golji
Oncology Drug Discovery, Novartis Institutes for BioMedical Research (NIBR), Cambridge, Massachusetts.
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Ailing Li
Oncology Drug Discovery, Novartis Institutes for BioMedical Research (NIBR), Cambridge, Massachusetts.
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Xiamei Zhang
Oncology Drug Discovery, Novartis Institutes for BioMedical Research (NIBR), Cambridge, Massachusetts.
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David A. Ruddy
Oncology Drug Discovery, Novartis Institutes for BioMedical Research (NIBR), Cambridge, Massachusetts.
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Daniel P. Rakiec
Oncology Drug Discovery, Novartis Institutes for BioMedical Research (NIBR), Cambridge, Massachusetts.
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Felipe C. Geyer
Oncology Drug Discovery, Novartis Institutes for BioMedical Research (NIBR), Cambridge, Massachusetts.
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Jane Gu
Oncology Drug Discovery, Novartis Institutes for BioMedical Research (NIBR), Cambridge, Massachusetts.
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Hui Gao
Oncology Drug Discovery, Novartis Institutes for BioMedical Research (NIBR), Cambridge, Massachusetts.
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Juliet A. Williams
Oncology Drug Discovery, Novartis Institutes for BioMedical Research (NIBR), Cambridge, Massachusetts.
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Darrin D. Stuart
Oncology Drug Discovery, Novartis Institutes for BioMedical Research (NIBR), Cambridge, Massachusetts.
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  • For correspondence: matthew.meyer@bms.com darrin.stuart@novartis.com
Matthew J. Meyer
Oncology Drug Discovery, Novartis Institutes for BioMedical Research (NIBR), Cambridge, Massachusetts.
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  • For correspondence: matthew.meyer@bms.com darrin.stuart@novartis.com
DOI: 10.1158/1535-7163.MCT-19-0028 Published December 2019
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Abstract

Inhibitors targeting BRAF and its downstream kinase MEK produce robust response in patients with advanced BRAFV600-mutant melanoma. However, the duration and depth of response vary significantly between patients; therefore, predicting response a priori remains a significant challenge. Here, we utilized the Novartis collection of patient-derived xenografts to characterize transcriptional alterations elicited by BRAF and MEK inhibitors in vivo, in an effort to identify mechanisms governing differential response to MAPK inhibition. We show that the expression of an MITF-high, “epithelial-like” transcriptional program is associated with reduced sensitivity and adaptive response to BRAF and MEK inhibitor treatment. On the other hand, xenograft models that express an MAPK-driven “mesenchymal-like” transcriptional program are preferentially sensitive to MAPK inhibition. These gene-expression programs are somewhat similar to the MITF-high and -low phenotypes described in cancer cell lines, but demonstrate an inverse relationship with drug response. This suggests a discrepancy between in vitro and in vivo experimental systems that warrants future investigations. Finally, BRAFV600-mutant melanoma relies on either MAPK or alternative pathways for survival under BRAF and MEK inhibition in vivo, which in turn predicts their response to further pathway suppression using a combination of BRAF, MEK, and ERK inhibitors. Our findings highlight the intertumor heterogeneity in BRAFV600-mutant melanoma, and the need for precision medicine strategies to target this aggressive cancer.

Footnotes

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

  • Mol Cancer Ther 2019;18:2421–32

  • Received January 8, 2019.
  • Revision received June 26, 2019.
  • Accepted September 10, 2019.
  • Published first September 16, 2019.
  • ©2019 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 18 (12)
December 2019
Volume 18, Issue 12
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Distinct Transcriptional Programming Drive Response to MAPK Inhibition in BRAFV600-Mutant Melanoma Patient-Derived Xenografts
Tianshu Feng, Javad Golji, Ailing Li, Xiamei Zhang, David A. Ruddy, Daniel P. Rakiec, Felipe C. Geyer, Jane Gu, Hui Gao, Juliet A. Williams, Darrin D. Stuart and Matthew J. Meyer
Mol Cancer Ther December 1 2019 (18) (12) 2421-2432; DOI: 10.1158/1535-7163.MCT-19-0028

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Distinct Transcriptional Programming Drive Response to MAPK Inhibition in BRAFV600-Mutant Melanoma Patient-Derived Xenografts
Tianshu Feng, Javad Golji, Ailing Li, Xiamei Zhang, David A. Ruddy, Daniel P. Rakiec, Felipe C. Geyer, Jane Gu, Hui Gao, Juliet A. Williams, Darrin D. Stuart and Matthew J. Meyer
Mol Cancer Ther December 1 2019 (18) (12) 2421-2432; DOI: 10.1158/1535-7163.MCT-19-0028
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Molecular Cancer Therapeutics
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