Destabilization of NOXA mRNA as a common resistance mechanism to targeted therapies

Joan Montero, Cécile Gstalder, Daniel J. Kim, Dorota Sadowicz, Wayne Miles, Michael Manos, Justin R. Cidado, J. Paul Secrist, Adriana E. Tron, Keith Flaherty, F. Stephen Hodi, Charles H. Yoon, Anthony Letai, David E. Fisher () and Rizwan Haq ()
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Joan Montero: Harvard Medical School
Cécile Gstalder: Harvard Medical School
Daniel J. Kim: Massachusetts General Hospital, Harvard Medical School
Dorota Sadowicz: Harvard Medical School
Wayne Miles: The Ohio State University
Michael Manos: Harvard Medical School
Justin R. Cidado: Bioscience, Oncology IMED Biotech Unit
J. Paul Secrist: Bioscience, Oncology IMED Biotech Unit
Adriana E. Tron: Bioscience, Oncology IMED Biotech Unit
Keith Flaherty: Harvard Medical School
F. Stephen Hodi: Harvard Medical School
Charles H. Yoon: Brigham and Women’s Hospital, Harvard Medical School
Anthony Letai: Harvard Medical School
David E. Fisher: Massachusetts General Hospital, Harvard Medical School
Rizwan Haq: Harvard Medical School

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Most targeted cancer therapies fail to achieve complete tumor regressions or attain durable remissions. To understand why these treatments fail to induce robust cytotoxic responses despite appropriately targeting oncogenic drivers, here we systematically interrogated the dependence of cancer cells on the BCL-2 family of apoptotic proteins after drug treatment. We observe that multiple targeted therapies, including BRAF or EGFR inhibitors, rapidly deplete the pro-apoptotic factor NOXA, thus creating a dependence on the anti-apoptotic protein MCL-1. This adaptation requires a pathway leading to destabilization of the NOXA mRNA transcript. We find that interruption of this mechanism of anti-apoptotic adaptive resistance dramatically increases cytotoxic responses in cell lines and a murine melanoma model. These results identify NOXA mRNA destabilization/MCL-1 adaptation as a non-genomic mechanism that limits apoptotic responses, suggesting that sequencing of MCL-1 inhibitors with targeted therapies could overcome such widespread and clinically important resistance.

Date: 2019
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DOI: 10.1038/s41467-019-12477-y

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