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Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models

Jo Waaler, Line Mygland, Anders Tveita, Martin Frank Strand, Nina Therese Solberg, Petter Angell Olsen, Kaja Lund, Shoshy Alam Brinch, Max Lycke, Elisabeth Dybing, Vegard Nygaard, Sigurd Laeines Boe, Karen-Marie Heintz, Eivind Hovig, Clara Hammarstrom, Alexandre Corthay, Stefan Krauss
doi: https://doi.org/10.1101/526343
Jo Waaler
Oslo University Hospital and University of Oslo;
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Line Mygland
Oslo University Hospital;
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  • For correspondence: linmyg@ous-hf.no
Anders Tveita
Oslo University Hospital;
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Martin Frank Strand
Kristiania University College
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Nina Therese Solberg
Oslo University Hospital;
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Petter Angell Olsen
Oslo University Hospital and University of Oslo;
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Kaja Lund
Oslo University Hospital;
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Shoshy Alam Brinch
Oslo University Hospital;
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Max Lycke
Oslo University Hospital;
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Elisabeth Dybing
Oslo University Hospital;
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Vegard Nygaard
Oslo University Hospital;
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Sigurd Laeines Boe
Oslo University Hospital;
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Karen-Marie Heintz
Oslo University Hospital;
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  • For correspondence: karen-marie.heintz@rr-research.no
Eivind Hovig
Oslo University Hospital;
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Clara Hammarstrom
Oslo University Hospital;
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  • For correspondence: chammars@ous-hf.no
Alexandre Corthay
Oslo University Hospital;
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Stefan Krauss
Oslo University Hospital and University of Oslo;
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  • For correspondence: stefan.krauss@rr-research.no
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Abstract

The development of immune checkpoint inhibitors represents a major breakthrough in cancer therapy. Nevertheless, a substantial number of patients fail to respond to checkpoint pathway blockade. β-catenin is the key transcriptional regulator of WNT/β-catenin signaling. Evidence for β-catenin-mediated immune evasion is found in 13% of all cancers, 42% of primary cutaneous melanoma and a mouse melanoma model. Currently, there are no therapeutic strategies available for targeting WNT/β-catenin signaling to counteract checkpoint inhibitor resistance in melanoma. Here we report that a specific small-molecule tankyrase inhibitor, G007-LK, attenuates WNT/β-catenin and YAP signaling pathways in the syngeneic murine B16-F10 melanoma model enabling sensitivity to anti-PD-1 immune checkpoint therapy. RNA sequencing of 18 tankyrase inhibitor-treated human melanoma cell lines and B16-F10 cells revealed a transcriptional response profile for a subpopulation. This cell line sub-group displayed elevated baseline YAP signaling activity and was susceptible to reduce melanocyte inducing transcription factor (MITF) expression upon tankyrase inhibition.

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Posted January 22, 2019.
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Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models
Jo Waaler, Line Mygland, Anders Tveita, Martin Frank Strand, Nina Therese Solberg, Petter Angell Olsen, Kaja Lund, Shoshy Alam Brinch, Max Lycke, Elisabeth Dybing, Vegard Nygaard, Sigurd Laeines Boe, Karen-Marie Heintz, Eivind Hovig, Clara Hammarstrom, Alexandre Corthay, Stefan Krauss
bioRxiv 526343; doi: https://doi.org/10.1101/526343
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Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models
Jo Waaler, Line Mygland, Anders Tveita, Martin Frank Strand, Nina Therese Solberg, Petter Angell Olsen, Kaja Lund, Shoshy Alam Brinch, Max Lycke, Elisabeth Dybing, Vegard Nygaard, Sigurd Laeines Boe, Karen-Marie Heintz, Eivind Hovig, Clara Hammarstrom, Alexandre Corthay, Stefan Krauss
bioRxiv 526343; doi: https://doi.org/10.1101/526343

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