Therapeutic Advantage of Targeting PRMT5 in Combination with Chemotherapies or EGFR/HER2 Inhibitors in Triple-Negative Breast Cancers.

Purpose: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subgroup characterized by a high risk of resistance to chemotherapies and high relapse potential. TNBC shows inter-and intra-tumoral heterogeneity; more than half expresses high EGFR levels and about 30% are classified as HER2-low breast cancers. High PRMT5 mRNA levels are associated with poor prognosis in TNBC and inhibiting PRMT5 impairs the viability of subsets of TNBC cell lines and delays tumor growth in TNBC mice models. TNBC patients may therefore benefit from a treatment targeting PRMT5. The aim of this study was to assess the therapeutic benefit of combining a PRMT5 inhibitor with different chemotherapies used in the clinics to treat TNBC patients, or with FDA-approved inhibitors targeting the HER family members. Methods: The drug combinations were performed using proliferation and colony formation assays on TNBC cell lines that were sensitive or resistant to EPZ015938, a PRMT5 inhibitor that has been evaluated in clinical trials. The chemotherapies analyzed were cisplatin, doxorubicin, camptothecin, and paclitaxel. The targeted therapies tested were erlotinib (EGFR inhibitor), neratinib (EGFR/HER2/HER4 inhibitor) and tucatinib (HER2 inhibitor). Results: We found that PRMT5 inhibition synergized mostly with cisplatin, and to a lesser extent with doxorubicin or camptothecin, but not with paclitaxel, to impair TNBC cell proliferation. PRMT5 inhibition also synergized with erlotinib and neratinib in TNBC cell lines, especially in those overexpressing EGFR. Additionally, a synergistic interaction was observed with neratinib and tucatinib in a HER2-low TNBC cell line as well as in a HER2-positive breast cancer cell line. We noticed that synergy can be obtained in TNBC cell lines that were resistant to PRMT5 inhibition alone. Conclusion: Altogether, our data highlight the therapeutic potential of targeting PRMT5 using combinatorial strategies for the treatment of subsets of TNBC patients.

Respective roles of Pik3ca mutations and cyproterone acetate impregnation in mouse meningioma tumorigenesis.

Despite their rarity, PIK3CA mutations in meningiomas have raised interest as potentially targetable, ubiquitous mutations owing to their presence in sporadic benign and malignant tumors but also in hormone-related cases. Using new genetically engineered mouse models, we here demonstrate that Pik3ca mutations in postnatal meningeal cells are sufficient to promote meningioma formation but also tumor progression in mice. Conversely, hormone impregnation, whether alone or in association with Pik3ca and Nf2 mutations, fails to induce meningioma tumorigenesis while promoting breast tumor formation. We then confirm in vitro the effect of Pik3ca mutations but not hormone impregnation on the proliferation of primary cultures of mouse meningeal cells. Finally, we show by exome analysis of breast tumors and meninges that hormone impregnation promotes breast tumor formation without additional somatic oncogenic mutation but is associated with an increased mutational burden on Pik3ca-mutant background. Taken together, these results tend to suggest a prominent role of Pik3ca mutations over hormone impregnation in meningioma tumorigenesis, the exact effect of the latter is still to be discovered.

Hexokinase 2 is a transcriptional target and a positive modulator of AHR signalling.

The aryl hydrocarbon receptor (AHR) regulates the expression of numerous genes in response to activation by agonists including xenobiotics. Although it is well appreciated that environmental signals and cell intrinsic features may modulate this transcriptional response, how it is mechanistically achieved remains poorly understood. We show that hexokinase 2 (HK2) a metabolic enzyme fuelling cancer cell growth, is a transcriptional target of AHR as well as a modulator of its activity. Expression of HK2 is positively regulated by AHR upon exposure to agonists both in human cells and in mice lung tissues. Conversely, over-expression of HK2 regulates the abundance of many proteins involved in the regulation of AHR signalling and these changes are linked with altered AHR expression levels and transcriptional activity. HK2 expression also shows a negative correlation with AHR promoter methylation in tumours, and these tumours with high HK2 expression and low AHR methylation are associated with a worse overall survival in patients. In sum, our study provides novel insights into how AHR signalling is regulated which may help our understanding of the context-specific effects of this pathway and may have implications in cancer.

PRMT1 Regulates EGFR and Wnt Signaling Pathways and Is a Promising Target for Combinatorial Treatment of Breast Cancer.

Identifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. Here, we found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. PRMT1 depletion decreases cell survival by inducing DNA damage and apoptosis in various breast cancer cell lines. Transcriptomic analysis and chromatin immunoprecipitation revealed that PRMT1 regulates the epidermal growth factor receptor (EGFR) and the Wnt signaling pathways, reported to be activated in TNBC. PRMT1 enzymatic activity is also required to stimulate the canonical Wnt pathway. Type I PRMT inhibitors decrease breast cancer cell proliferation and show anti-tumor activity in a TNBC xenograft model. These inhibitors display synergistic interactions with some chemotherapies used to treat TNBC patients as well as erlotinib, an EGFR inhibitor. Therefore, targeting PRMT1 in combination with these chemotherapies may improve existing treatments for TNBC patients.

CARM1/PRMT4: Making Its Mark beyond Its Function as a Transcriptional Coactivator.

Coactivator-associated arginine methyltransferase 1 (CARM1), identified 20 years ago as a coregulator of transcription, is an enzyme that catalyzes arginine methylation of proteins. Beyond its well-established involvement in the regulation of transcription, the physiological functions of CARM1 are still poorly understood. However, recent studies have revealed novel roles of CARM1 in autophagy, metabolism, paraspeckles, and early development. In addition, CARM1 is emerging as an attractive therapeutic target and a drug response biomarker for certain types of cancer. Here, we provide a comprehensive overview of the structure of CARM1 and its post-translational modifications, its various functions, apart from transcriptional coactivation, and its involvement in cancer.