Smyca-FOXM1 ribonucleoprotein complex promotes homologous recombination and tumor immune evasion to define a therapeutic target of triple-negative breast cancer

Abstract

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited treatment options. Although PARP inhibitor (PARPi) offers great promise in treating TNBC with deficiency in homologous recombination (HR), most TNBC patients are HR-proficient. Furthermore, acquired resistance to PARPi remains as a challenge. Thus, there is an unmet need to identify new therapeutic target for developing advanced TNBC treatment strategy. METHODS: I-SceI reporter assay and alkaline comet assay were used to analyze the role of Smyca in HR repair. Ingenuity pathway analysis was used to identify upstream regulators of Smyca-regulated transcriptome. RNA immunoprecipitation and RNA pull down were used to examine Smyca-FOXM1 interaction. Chromatin immunoprecipitation followed by sequencing was performed to identify FOXM1 target genes that are regulated by Smyca. Chromatin isolation by RNA purification was used to determine Smyca loading onto the promoters of FOXM1 target genes. Patient-derived organoid and xenograft mouse models were performed to evaluate the effect of Smyca on chemoresistance. Nanoparticle-assisted gapmer antisense oligonucleotides delivery was used to target Smyca in vivo. Co-culture of CD3 + T cells with TNBC cells and syngeneic mouse model were used to examine the effect of Smyca-FOXM1 targeting on anti-tumor immunity. RESULTS: The long non-coding RNA Smyca is highly expressed in TNBC. We show that Smyca is induced by genotoxic agents to enhance HR repair. Mechanistically, Smyca binds FOXM1 and promotes the recruitment of FOXM1 to the promoters of a set of HR and nucleotide metabolism genes, thereby promoting their expression. Smyca ablation induces BRCAness in HR-proficient TNBC, thereby sensitizing these tumors to platinum or PARPi. Furthermore, targeting Smyca-FOXM1 complex in combination with platinum or PARPi activates cGAS/STING pathway and tumor immunogenicity to enhance anti-tumor immune surveillance. Clinically, Smyca expression in breast cancer patients correlates positively with therapy resistance and negatively with HR deficiency, interferon signature, and infiltration of anti-tumor immune cells. CONCLUSIONS: Our study identifies an unprecedented role of Smyca in HR repair to promote TNBC survival and immune evasion in response to therapy and suggests Smyca as a potential target for sensitizing TNBC to chemotherapy, PARPi, or immunotherapy.