Inhibitory Effect of PRMT5/MTA Inhibitor on MTAP-Deficient Glioma May Be Influenced by Surrounding Normal Cells.

Methylthioadenosine phosphorylase (MTAP) and protein arginine methyltransferase 5 (PRMT5) are considered to be a synthetic lethal pair of targets, due to the fact that deletion of MTAP leads to massive production of methylthioadenosine (MTA) decreasing the activity of PRMT5. In vitro and in vivo experiments have demonstrated that MRTX1719, a small molecule that selectively binds PRMT5/MTA complex, significantly inhibits the proliferation of MTAP-deficient tumors and has a weak toxic effect on normal cells. However, it has been reported that MTAP-deleted tumors did not significantly accumulate MTA in vivo due to metabolism of MTA by MTAP-expressing stroma, which might lead to a diminished anti-cancer effect of MRTX1719. We first analyzed whether there were MTAP-expressing normal intracerebral cells around MTAP-deficient glioma tissues by paraffin-embedded tissue microarray of human glioma specimens. Then, in vivo and in vitro models of MTAP-deficient gliomas coexisting with neurons or glial cells were constructed for evaluating the effectiveness of the anti-tumor effects of MRTX1719 in this setting. MTAP-deficient gliomas were surrounded by a large number of MTAP-expressing normal cells, and the presence of these cells significantly reduced the inhibitory effect of MRTX1719 on MTAP-deficient glioma cells in vitro and in vivo. Due to the complexity of the tumor environment in vivo, the anti-tumor effects of PRMT5/MTA-specific inhibitors may be somewhat attenuated, and their ability to achieve suitable therapeutic effects in the clinic might require more in-depth studies.

Wang Y ，Sun X ，Ma R ，Zhang X ，Ji S ，Liu Z ，Yang G ，Wang H ，Zhang P ，Zhang J ，Tian J ... -  《Cancer Medicine》

MRTX1719, an MTA-cooperative PRMT5 Inhibitor, Induces Cell Cycle Arrest and Synergizes With Oxaliplatin and Gemcitabine for Enhanced Anticancer Effects.

MRTX1719 is a novel protein arginine methyltransferase 5 (PRMT5) inhibitor that targets the PRMT5-5'-Methylthioadenosine (MTA) complex called MTA-cooperative PRMT5 inhibitor. MRTX1719 acts specifically on methylthioadenosine phosphorylase (MTAP)-deficient cancer cells; however, its mechanism of action remains unclear. This study aimed to clarify the effects of MRTX1719 on the cell cycle and its synergistic effects with other anticancer drugs. A cell cycle assay was conducted using fluorescence-activated cell sorting to examine the correlation between PRMT5 activity and cells in the G0/G1 phase. The synergistic effects of MRTX1719 and anticancer drugs were evaluated using the Combination Index (CI) and Bliss synergy score (BSS). The synergistic effect was also evaluated by knocking down the endogenous expression of MTAP in HCT116 cells with high MTAP expression. The cell cycle assay showed that the population of cells with reduced PRMT5 activity increased, and the administration of MRTX1719, an MTAP inhibitor, increased the population of cells in the G0/G1 phase. In the synergistic effect assay, oxaliplatin and gemcitabine demonstrated a CI <1 and a BSS >0, indicating a synergistic effect when administered alongside MRTX1719. MTAP knockdown also resulted in <1 in CI and >0 in BSS after the administration of oxaliplatin or gemcitabine with MRTX1719. MRTX1719 reduces PRMT5 activity, leading to cell cycle arrest by increasing the proportion of cells in the G0/G1 phase. Moreover, MRTX1719 exhibits synergistic anticancer effects with oxaliplatin and gemcitabine in MTAP-deficient cancer cells.

Soeta T ，Sugisawa N ，Yamamura A ，Tanaka N ，Imoto H ，Tsuchiya T ，Aizawa T ，Okamoto K ，Kawamura M ，Saijo F ，Mizuma M ，Ohnuma S ，Kamei T ，Unno M ... -  《-》

First-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP-deleted solid tumors: results from phase I dose exploration.

Rodon J ，Prenen H ，Sacher A ，Villalona-Calero M ，Penel N ，El Helali A ，Rottey S ，Yamamoto N ，Ghiringhelli F ，Goebeler ME ，Doi T ，Postel-Vinay S ，Lin CC ，Liu C ，Chuang CH ，Keyvanjah K ，Eggert T ，O'Neil BH ... -  《-》

Gambogic acid impairs the maintenance and therapeutic resistance of glioma stem cells by targeting B-cell-specific Moloney leukemia virus insert site 1.

Glioblastoma (GBM) is the most common and lethal primary brain tumor with low effectiveness of available treatments. The tumor heterogeneity and therapeutic resistance are largely due to the presence of glioma stem cells (GSCs). Therefore, eliminating GSCs can overcome the progression, relapse, and resistance of GBM. Previous studies have shown that gambogic acid (GA), a natural active ingredient, has anti-glioma properties. Nonetheless, it is still unclear whether it has an inhibitory effect on GSCs and what its target might be. This study aimed to investigate the anti-tumor effects of GA on GSCs. In addition, this study found the target of GA in GSCs and elucidated the potential specific mechanisms by conducting both in vitro and in vivo experiments. B-cell-specific Moloney leukemia virus insert site 1 (BMI1) is a key stem cell factor of the polycomb group (PcG) family with important effects on the development, recurrence, and chemoresistance of several cancers. In both normal and cancer stem cells, BMI1 maintains stem cell self-renewal by regulating the cell cycle, cellular immortalization, and senescence. Its high expression in a variety of cancers correlates with poor clinical prognosis and chemoresistance. These mechanisms of BMI1 make it a potential therapeutic target for cancer therapy, and future studies may further reveal the specific roles of BMI1 mechanism and provide a basis for the development of new cancer therapeutic strategies. This study investigated the in vitro and in vivo effects of GA in inducing apoptosis in GSCs and inhibiting GSCs self-renewal, as well as its underlying mechanisms. This study synthesized biotinylated gambogic acid for the first time and angled for the target of gambogic acid using LC-MS/MS analysis, which has not been reported previously. Human-derived glioma stem cells GSC123 and GSC111 were used for in vitro studies, analyzing functions and mechanisms via microscale thermophoresis (MST), Annexin V/PI staining, Western blotting, immunofluorescence, and co-immunoprecipitation. The orthotopic glioma mouse model was used to assess the anti-tumor effects of GA in vivo. This study demonstrated that GA is a specific inhibitor of BMI1, a key regulator controlling stem cell growth and self-renewal. GA binds to BMI1's RING domain, accelerating K51-dependent degradation and suppressing H2A ubiquitination. Importantly, GA induces apoptosis, and inhibits GSC self-renewal, but minimally impacts neural progenitor cells (NPCs). GA can also be combined effectively with temozolomide and radiotherapy to increase their sensitivities in resistant cells. Furthermore, exogenous induction of BMI1 expression significantly hinders the disruption of GSCs by GA. In vivo, GA inhibits tumorigenicity, enhances the effect of temozolomide, and reduces BMI1 expression. These findings suggest that GA is a potential candidate for targeting GSCs and therefore be used to treat GBM.

Sun T ，Lin B ，Sun Q ，Zhang X ，Wang T ，Yang J ，Liu X ，Lu H ，Lu N ，Zhao K ... -  《-》

Identification of PRMT5 as a therapeutic target in cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a very difficult-to-treat cancer. Chemotherapies are little effective and response to immune checkpoint inhibitors is limited. Therefore, new therapeutic strategies need to be identified. We characterised the enzyme protein arginine-methyltransferase 5 (PRMT5) as a novel therapeutic target in CCA. We evaluated the expression of PRMT5, its functional partner MEP50 and methylthioadenosine phosphorylase (MTAP)-an enzyme that modulates the sensitivity of PRMT5 to pharmacological inhibitors-in human CCA tissues. PRMT5-targeting drugs, currently tested in clinical trials for other malignancies, were assessed in human CCA cell lines and organoids, as well as in two immunocompetent CCA mouse models. Transcriptomic, proteomic and functional analyses were performed to explore the underlying antitumoural mechanisms. PRMT5 and MEP50 proteins were correlatively overexpressed in most CCA tissues. MTAP was absent in 25% of intrahepatic CCA. PRMT5-targeting drugs markedly inhibited CCA cell proliferation, synergising with cisplatin and gemcitabine and hindered the growth of cholangiocarcinoma organoids. PRMT5 inhibition blunted the expression of oncogenic genes involved in chromatin remodelling and DNA repair, consistently inducing the formation of RNA loops and promoting DNA damage. Treatment with PRMT5-targeting drugs significantly restrained the growth of experimental CCA without adverse effects and concomitantly induced the recruitment of CD4 and CD8 T cells to shrinking tumourous lesions. PRMT5 and MEP50 are frequently upregulated in human CCA, and PRMT5-targeting drugs have significant antitumoural efficacy in clinically relevant CCA models. Our findings support the evaluation of PRMT5 inhibitors in clinical trials, including their combination with cytotoxic and immune therapies.

Elurbide J ，Colyn L ，Latasa MU ，Uriarte I ，Mariani S ，Lopez-Pascual A ，Valbuena E ，Castello-Uribe B ，Arnes-Benito R ，Adan-Villaescusa E ，Martinez-Perez LA ，Azkargorta M ，Elortza F ，Wu H ，Krawczyk M ，Schneider KM ，Sangro B ，Aldrighetti L ，Ratti F ，Casadei Gardini A ，Marin JJG ，Amat I ，Urman JM ，Arechederra M ，Martinez-Chantar ML ，Trautwein C ，Huch M ，Cubero FJ ，Berasain C ，G Fernandez-Barrena M ，Avila MA ... -  《-》