PRMT inhibition induces a viral mimicry response in triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and few effective therapies. Here we identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs), which has antitumor growth activity in TNBC. Pathway analysis of TNBC cell lines indicates that the activation of interferon responses before and after MS023 treatment is a functional biomarker and determinant of response, and these observations extend to a panel of human-derived organoids. Inhibition of type I PRMT triggers an interferon response through the antiviral defense pathway with the induction of double-stranded RNA, which is derived, at least in part, from inverted repeat Alu elements. Together, our results represent a shift in understanding the antitumor mechanism of type I PRMT inhibitors and provide a rationale and biomarker approach for the clinical development of type I PRMT inhibitors.

Challenges for Triple Negative Breast Cancer Treatment: Defeating Heterogeneity and Cancer Stemness

“…Indeed, a viral mimicry response can be induced when using epigenetic inhibitors (histone methyltransferase EZH2 and PRMT1 inhibitors) that induce the expression of transposable element-derived double-stranded RNA. Such a response is able to activate an interferon response resulting in a potent antitumour effect [ 83 ]. Furthermore, a study has recently linked H3K4me3 (trimethylation of histone H3 at lysine 4) and H3K27me3 (trimethylation of histone H3 at lysine 27) to the persister cell population expression program in TNBC tumours.…”

Dark genome, bright ideas: Recent approaches to harness transposable elements in immunotherapies

“…Finally, it is important to note that TEs are not necessarily transcribed in an autonomous fashion, and a large fraction are found in introns. Moreover, de novo integration of TEs into exons or alternative splicing events allowing readthrough of intronic TEs (Wu et al, 2022) can generate fusion proteins that could serve as targetable antigens. Overall, TEs represent a specific source of immunogenic tumor antigens that can be recognized by T cells and induce a functional response (Laumont et al, 2018;Saini et al, 2020;Ehx et al, 2021) (Griffin et al, 2021).…”

“…Zhang et al demonstrated that inhibition of CDK9 led to the dephosphorylation of BRG1, a regulator of heterochromatin, and resulted in increased global gene expression, including expression of ERVs and IFN-I-associated signature (Zhang et al, 2018). Further, Wu et al demonstrated that inhibition of type I PRMTs in triple-negative breast cancer cell lines triggered aberrant splicing events, including the retention of introns containing IR-Alus that can form dsRNA, contributing to the induction of an IFN-I response (Wu et al, 2022). This work (Choi et al, 2021).…”

“…TLR3, a cell surface and endosomal receptor that can also sense dsRNA, was also shown to sense TE-derived RNA. In human breast cancer cell lines MCF7 (Sheng et al, 2018) and MDA-MB-468 (Wu et al, 2022), silencing TLR3 impaired ISG activation induced by the knockdown of LSD1, an epigenetic suppressor of ERVs (Sheng et al, 2018) or by the inhibition of PRMT1 (Wu et al, 2022), respectively. Importantly, TLR3 is a sensor found both at the cell surface and in endosomes, and its activation indicates the uptake of TE-derived dsRNA from other cells or translocation of dsRNA from the cytosol into endosomes.…”

“…Investigation of RIG-I as a sensor of TE expression has been more limited than MDA5, and reports have been conflicting, with some studies demonstrating an absence or little impact on interferon stimulated genes (ISGs) activation following RIG-I downregulation (Sheng et al, 2018;Tunbak et al, 2020;Choi et al, 2021). However, ISG activation in triplenegative breast cancer cell lines treated with a protein arginine methyltransferase (PRMT) inhibitor, which alters mRNA splicing and induces intronic retention of IR-Alus, was significantly reduced after RIG-I silencing (Wu et al, 2022). More generally, the fact that several types of TEs, including most evolutionarily recent Alu families, are primarily transcribed by RNA polymerase III, which generates uncapped RNA that can retain 5 0 -PPP moieties, suggests a possible role of RIG-I in sensing these TE families.…”