A biomarker-driven approach to targeting polyamine depletion in triple negative breast cancer.

Abstract

Background: Triple negative breast cancer (TNBC) is the most aggressive and heterogenous breast cancer subtype. Polyamines are essential for TNBC growth and proliferation; however, therapeutic strategies targeting polyamine metabolism have shown limited efficacy in TNBC. In this study, we demonstrate a biomarker-driven approach to treating TNBC through polyamine depletion. As the rate limiting catabolic enzyme in the polyamine pathway, spermidine/spermine N¹-acetlytransferase (SAT1) reduces polyamines and generates the metabolite, diacetylspermine.

Methods: TNBC cell lines, ex vivo tumor slices, and in vivo patient-derived xenograft (PDX) models with low, moderate and high baseline levels of SAT1 were used to determine whether the efficacy of polyamine depletion therapy depends on their SAT1 metabolic phenotype.

Results: TNBC with high baseline SAT1 expression was sensitive to the SAT1 agonist N¹, N¹¹-diethylnorspermine (DENSpm) resulting in reduced cell viability, polyamine depletion and elevated diacetylspermine production. Cell viability in moderate baseline SAT1 expressing TNBC was further reduced by combining DENSpm with both therapeutic and subtherapeutic doxorubicin treatment. In vivo, the addition of DENSpm to doxorubicin treatment further attenuated tumor growth in moderate SAT1 expressing TNBC-PDX, which corresponded to a sustained increase in urine diacetylspermine as a biomarker of treatment effectiveness. Mechanism delineating experiments demonstrated that doxorubicin induces SAT1 expression while DENSpm promotes productive splicing, effectively increasing and sustaining SAT1 function, depleting polyamines and increasing diacetylspermine production.

Conclusions: In conclusion, these findings suggest that an SAT1-defined metabolic phenotype may enable a precision-guided strategy to effectively target polyamine depletion as a TNBC treatment and that treatment effectiveness may be monitored through evaluation of urine diacetylspermine as a non-invasive biomarker of treatment response.