Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. Chemotherapy before or after surgery remains the standard treatment regimen for stage I–III TNBC. Only a small portion of patients can benefit from targeted therapy with PARP inhibitors because of BRCA mutations. However, resistance to chemotherapy or targeted therapy remains a major hurdle.
In a new study published in the Journal of Biomedical Science, researchers at National Taiwan University, Academia Sinica and Taipei Medical University report that a little-known RNA molecule renders TNBC resistant to therapy. This RNA, Smyca, is a long noncoding RNA (lncRNA) expressed at high levels in TNBC. Unlike conventional RNAs that provide instructions for making proteins, lncRNAs often fine-tune gene expression to regulate cellular processes.
The researchers discovered that Smyca becomes even more abundant when TNBC is treated with DNA damage-inducing therapies. Moreover, Smyca promotes the repair of damaged DNA by working closely with FOXM1, an oncogenic transcription factor. In particular, Smyca directs FOXM1 to activate the transcription of a set of DNA repair and nucleotide metabolism genes, which supply repair machinery and DNA building blocks that allow tumor cells to recover from treatment-induced DNA damage.
Thus, Smyca controls a tumor-intrinsic defense program that facilitates escape from chemotherapy and targeted therapy—a discovery that could point toward new ways to make resistant tumors more responsive to existing treatment regimens.
To prove this concept, the researchers blocked Smyca functions using antisense RNA and nanoparticle-assisted delivery of antisense RNA to tumors. This strategy greatly inhibits DNA repair and sensitizes TNBC to chemotherapy and targeted therapy. Furthermore, Smyca targeting activates a potent immune defense against tumors. When Smyca targeting is combined with chemotherapy or targeted therapy, the accumulated DNA damage activates the cGAS–STING pathway, an immune-sensing system that alerts the body to abnormal cells.
Consequently, tumor immunogenicity is elevated and infiltration of immune cells into tumors is enhanced, thereby promoting the eradication of tumor cells. These responses also convert an immune-cold tumor microenvironment into an immune-hot one, which is known to sensitize tumors to immunotherapy, a standard regimen for treating stage IV TNBC.
"What makes this finding particularly important is that Smyca appears to connect two major mechanisms that allow tumors to survive therapy, namely DNA repair and immune escape," says co-corresponding author Ruey-Hwa Chen of the Institute of Biological Chemistry, Academia Sinica, and the Institute of Biochemical Sciences, National Taiwan University.
"By targeting this lncRNA pathway, we may be able to weaken the ability of tumors to repair treatment-induced DNA damage and simultaneously make them more exposed to the immune system."
Provided by National Taiwan University