NOS inhibition sensitizes metaplastic breast cancer to alpelisib and taxane chemotherapy by reversing cJUN-mediated epithelial-to-mesenchymal transition.

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 directly acts on 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 PDX models relative to single-/dual-agent therapy. Similarly, biopsies from MpBC tumors that responded to L-NMMA+taxane therapy showed post-treatment a reversal of epithelial-to-mesenchymal transition (EMT) and decreased stemness. Our findings suggest that combined inhibition of iNOS and PI3K is a novel strategy to decrease chemoresistance and improve clinical outcomes in MpBC.