Combination PI3K and NOS targeted therapy for metaplastic breast cancer

Abstract

Background: Metaplastic breast cancer (MBC) is a highly chemoresistant cancer, accounting for <1% of all breast cancers. Most MBCs typically display a triple-negative breast cancer (TNBC) phenotype, yet MBC exhibits a worse prognosis than TNBC and a dismal survival rate. The current mainstay of treatment include surgery and systemic chemotherapy, despite its chemofractory nature. A common molecular alteration in MBC is hyperactivation of the phosphoinositide 3-kinase (PI3K) pathway. We published that MBC displays a gain-of-function oncogenic mutation in ribosomal protein L39 (RPL39), which is responsible for treatment resistance, stem cell self-renewal, and lung metastasis. The mechanistic function of RPL39 is mediated through inducible nitric oxide synthase (iNOS)-mediated nitric oxide production. In addition, we demonstrated that inhibiting the NOS pathway using pan-NOS inhibitor NG-methyl-L-arginine acetate (L-NMMA) represents a highly effective therapeutic option for MBC patients. Alpelisib, an FDA-approved, isoform-specific PI3K inhibitor, is currently used with antiestrogen therapy, to treat hormone receptor (HR)-positive, PIK3CA-mutated breast cancer patients. Therefore, we hypothesize that the combinatorial approach of inhibiting the two major pathways implicated in MBC, namely PI3K and NOS pathways, would lead to significant tumor regression.