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Extracellular signal-regulated kinase mediates chromatin rewiring and lineage transformation in lung cancer

Yusuke Inoue, Ana Nikolic, Dylan Farnsworth, Alvin Liu, Marc Ladanyi, Romel Somwar, View ORCID ProfileMarco Gallo, William W. Lockwood
doi: https://doi.org/10.1101/2020.11.12.368522
Yusuke Inoue
1Department of Integrative Oncology, BC Cancer Agency, Canada
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Ana Nikolic
2Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB
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Dylan Farnsworth
1Department of Integrative Oncology, BC Cancer Agency, Canada
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Alvin Liu
1Department of Integrative Oncology, BC Cancer Agency, Canada
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Marc Ladanyi
3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, USA
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Romel Somwar
3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, USA
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Marco Gallo
2Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB
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  • ORCID record for Marco Gallo
William W. Lockwood
1Department of Integrative Oncology, BC Cancer Agency, Canada
4Department of Pathology & Laboratory Medicine, University of British Columbia, Canada
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  • For correspondence: wlockwood@bccrc.ca
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Abstract

Summary Lineage transformation between lung cancer subtypes is a poorly understood phenomenon associated with resistance to treatment and poor patient outcomes. Here, we aimed to model this transition to define underlying biological mechanisms and identify potential avenues for therapeutic intervention. Small cell lung cancer (SCLC) is neuroendocrine in origin and, in contrast to non-SCLC (NSCLC), rarely contains mutations that drive the MAPK pathway. Likewise, NSCLCs that transform to SCLC concomitantly with development of therapy resistance downregulate MAPK signaling, suggesting an inverse relationship between pathway activation and lineage state. To test this, we activated MAPK in SCLC through conditional expression of mutant KRAS or EGFR, which revealed suppression of the neuroendocrine differentiation program via ERK. We found that ERK induces the expression of ETS factors that mediate transformation into a NSCLC-like state. ATAC-seq demonstrated ERK-driven changes in chromatin accessibility at putative regulatory regions and global chromatin rewiring at neuroendocrine and ETS transcriptional targets. Further, ERK-mediated induction of ETS factors as well as suppression of neuroendocrine differentiation were dependent on histone acetyltransferase activities of CBP/p300. Overall, we describe how the ERK-CBP/p300-ETS axis promotes a lineage shift between neuroendocrine and non-neuroendocrine lung cancer phenotypes and provide rationale for the disruption of this program during transformation-driven resistance to targeted therapy.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 13, 2020.
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Extracellular signal-regulated kinase mediates chromatin rewiring and lineage transformation in lung cancer
Yusuke Inoue, Ana Nikolic, Dylan Farnsworth, Alvin Liu, Marc Ladanyi, Romel Somwar, Marco Gallo, William W. Lockwood
bioRxiv 2020.11.12.368522; doi: https://doi.org/10.1101/2020.11.12.368522
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Extracellular signal-regulated kinase mediates chromatin rewiring and lineage transformation in lung cancer
Yusuke Inoue, Ana Nikolic, Dylan Farnsworth, Alvin Liu, Marc Ladanyi, Romel Somwar, Marco Gallo, William W. Lockwood
bioRxiv 2020.11.12.368522; doi: https://doi.org/10.1101/2020.11.12.368522

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