NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression
T. P. 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 R. Rosato, Karina Ortega Martinez, Maria Florencia Chervo, Camila Ayerbe, Noah Giese, David A. Wink, Stephen Lockett, Stephen T.C. Wong, Jeffrey T. Chang, Savitri Krishnamurthy, Clinton Yam, Stacy L. Moulder, Helen Piwnica‐Worms, Funda Meric‐Bernstam, Jenny C. Chang, Jenny C. Chang, Jenny C. Chang
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 NH 2 -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.