NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression

Tejaswini Reddy, Akshjot Puri, Liliana Guzman-Rojas, Christoforos Thomas, Wei Qian, Jianying Zhou, Hong Zhao, Bijan Mahboubi, Adrian Oo, Young-Jae Cho, Baek Kim, Jose Thaiparambil, Roberto Rosato, Karina Ortega Martinez, Maria Florencia Chervo, Camila Ayerbe, Noah Giese, David Wink, Stephen Lockett, Stephen Wong, Jeffrey Chang, Savitri Krishnamurthy, Clinton Yam, Stacy Moulder, Helen Piwnica-Worms, Funda Meric-Bernstam and Jenny Chang ()
Additional contact information
Tejaswini Reddy: Baylor College of Medicine
Akshjot Puri: Houston Methodist Research Institute
Liliana Guzman-Rojas: Houston Methodist Research Institute
Christoforos Thomas: Houston Methodist Research Institute
Wei Qian: Houston Methodist Research Institute
Jianying Zhou: Houston Methodist Research Institute
Hong Zhao: Houston Methodist Research Institute
Bijan Mahboubi: University of North Carolina
Adrian Oo: Emory University
Young-Jae Cho: Emory University
Baek Kim: Emory University
Jose Thaiparambil: Houston Methodist Research Institute
Roberto Rosato: Houston Methodist Research Institute
Karina Ortega Martinez: Houston Methodist Research Institute
Maria Florencia Chervo: Houston Methodist Research Institute
Camila Ayerbe: The University of Texas Health Science Center
Noah Giese: Houston Methodist Research Institute
David Wink: National Institute of Health
Stephen Lockett: National Institutes of Health
Stephen Wong: Houston Methodist Research Institute
Jeffrey Chang: The University of Texas Health Science Center
Savitri Krishnamurthy: The University of Texas MD Anderson Cancer Center
Clinton Yam: The University of Texas MD Anderson Cancer Center
Stacy Moulder: Eli Lilly and Company
Helen Piwnica-Worms: The University of Texas MD Anderson Cancer Center
Funda Meric-Bernstam: The University of Texas MD Anderson Cancer Center
Jenny Chang: Houston Methodist Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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 NH2-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.

Date: 2024
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DOI: 10.1038/s41467-024-54651-x

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