NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression
Metaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor efficacy of taxane. We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane. Mechanistically, NOS blockade leads to a decrease in the S-nitrosylation of c-Jun NH<sub>2</sub>-terminal kinase (JNK)/c-Jun complex to repress its transcriptional output, leading to enhanced tumor differentiation and associated chemosensitivity. As a result, combined NOS and PI3K inhibition with taxane targets MpBC stem cells and improves survival in patient-derived xenograft models relative to single-/dual-agent therapy. Similarly, biopsies from MpBC tumors that responded to L-NMMA+taxane therapy showed a post-treatment reversal of epithelial-to-mesenchymal transition and decreased stemness. Our findings suggest that combined inhibition of iNOS and PI3K is a unique strategy to decrease chemoresistance and improve clinical outcomes in MpBC.
Authors
- Jeffrey T. Chang (ORCID: https://orcid.org/0000-0002-4578-5636)
- Tejaswini Parlapalle Reddy (ORCID: https://orcid.org/0000-0003-1806-1701)
- Christoforos Thomas (ORCID: https://orcid.org/0000-0003-3003-2954)
- Stephen Lockett (ORCID: https://orcid.org/0000-0002-2010-9914)
- Camila Ayerbe
- Stephen T.C. Wong (ORCID: https://orcid.org/0000-0001-9188-6502)
- Baek Kim (ORCID: https://orcid.org/0000-0001-7986-4335)
- Maria Florencia Chervo
- Jenny C. Chang (ORCID: https://orcid.org/0000-0002-0890-9302)
- Savitri Krishnamurthy (ORCID: https://orcid.org/0000-0001-9030-4136)
- Jose Thaiparambil (ORCID: https://orcid.org/0000-0002-5038-7114)
- Stacy L. Moulder (ORCID: https://orcid.org/0009-0004-6078-2769)
- David A. Wink (ORCID: https://orcid.org/0000-0002-5652-7480)
- Young‐Jae Cho (ORCID: https://orcid.org/0000-0001-6943-4462)
- Bijan Mahboubi (ORCID: https://orcid.org/0000-0001-6480-7581)
- Jianying Zhou (ORCID: https://orcid.org/0000-0002-8924-935X)
- Clinton Yam (ORCID: https://orcid.org/0000-0002-0809-0851)
- Noah Giese (ORCID: https://orcid.org/0000-0002-0027-2239)
- Liliana Guzman‐Rojas
- Akshjot Puri (ORCID: https://orcid.org/0000-0001-7187-7561)
- Helen Piwnica‐Worms (ORCID: https://orcid.org/0000-0003-4210-6738)
- Funda Meric‐Bernstam (ORCID: https://orcid.org/0000-0001-6816-6072)
- Adrian Oo (ORCID: https://orcid.org/0000-0002-2469-5391)
- Hong Zhao (ORCID: https://orcid.org/0000-0001-8991-7824)
- Wei Qian (ORCID: https://orcid.org/0000-0002-2970-5069)
- Roberto R. Rosato (ORCID: https://orcid.org/0000-0002-7885-5127)
- Karina Ortega Martinez
Institutions
- University of North Carolina at Chapel Hill (US)
- Houston Methodist (US)
- National Institutes of Health (US)
- The University of Texas MD Anderson Cancer Center (US)
- Emory University (US)
- Eli Lilly (United States) (US)
- Baylor College of Medicine (US)
- Methodist Hospital (US)
- Methodist Hospital (US)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-30
- DOI
- https://doi.org/10.1038/s41467-024-54651-x
- Citations
- 8
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 2.28
Funders
- Breast Cancer Research Foundation
- Houston Methodist Research Institute
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases