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Nat Commun. 2019 Nov 14;10(1):5157. doi: 10.1038/s41467-019-12477-y.

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

Author information

1
Division of Hematologic Neoplasia/Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA.
3
Institute for Bioengineering of Catalonia, C/Baldiri Reixac 15-21, Ed. Hèlix 3ª planta · 08028, Barcelona, Spain.
4
Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA.
5
Department of Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, 44 Fruit Street, Boston, MA, 02114, USA.
6
Department of Molecular Genetics, The Ohio State University, 820 Biomedical Research Tower 460 West 12th Avenue, Columbus, 43210, OH, USA.
7
Bioscience, Oncology IMED Biotech Unit, AstraZeneca, 35 Gatehouse Dr, Waltham, Boston, 02451, MA, USA.
8
LifeMine Therapeutics, 100 Acorn Park Drive, 6th Floor Cambridge, Cambridge, MA, 02140, USA.
9
Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, 44 Fruit Street, Boston, MA, 02114, USA.
10
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, 02115, USA.
11
Department of Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, 44 Fruit Street, Boston, MA, 02114, USA. dfisher3@partners.org.
12
Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, 44 Fruit Street, Boston, MA, 02114, USA. dfisher3@partners.org.
13
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA. rizwan_haq@dfci.harvard.edu.
14
Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA. rizwan_haq@dfci.harvard.edu.

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.

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