Dakroub Rayan, Huard Solène, Hajj-Younes Yara, Suresh Samyuktha, Badran Bassam, Fayyad-Kazan Hussein, Dubois Thierry
Breast Cancer Biology Group, Translational Research Department, Institut Curie-PSL Research University, Paris, 75005, France.
Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences-I, Lebanese University, Hadath, 1003, Lebanon.
Breast Cancer (Dove Med Press). 2023 Nov 6;15:785-799. doi: 10.2147/BCTT.S430513. eCollection 2023.
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.
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).
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.
Altogether, our data highlight the therapeutic potential of targeting PRMT5 using combinatorial strategies for the treatment of subsets of TNBC patients.
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚组，其特点是对化疗耐药风险高且复发潜力大。TNBC表现出肿瘤间和肿瘤内的异质性；超过一半的患者EGFR水平高，约30%被归类为HER2低表达乳腺癌。PRMT5 mRNA水平高与TNBC预后不良相关，抑制PRMT5会损害TNBC细胞系亚群的活力，并延缓TNBC小鼠模型中的肿瘤生长。因此，TNBC患者可能受益于针对PRMT5的治疗。本研究的目的是评估将PRMT5抑制剂与临床上用于治疗TNBC患者的不同化疗药物，或与FDA批准的靶向HER家族成员的抑制剂联合使用的治疗效果。
使用增殖和集落形成试验对TNBC细胞系进行药物联合实验，这些细胞系对已在临床试验中评估的PRMT5抑制剂EPZ015938敏感或耐药。分析的化疗药物有顺铂、阿霉素、喜树碱和紫杉醇。测试的靶向治疗药物有厄洛替尼（EGFR抑制剂）、奈拉替尼（EGFR/HER2/HER4抑制剂）和图卡替尼（HER2抑制剂）。
我们发现，抑制PRMT5主要与顺铂协同作用，在较小程度上与阿霉素或喜树碱协同作用，但与紫杉醇无协同作用，可损害TNBC细胞增殖。在TNBC细胞系中，抑制PRMT5也与厄洛替尼和奈拉替尼协同作用，尤其是在那些EGFR过表达的细胞系中。此外，在HER2低表达的TNBC细胞系以及HER2阳性乳腺癌细胞系中，观察到奈拉替尼和图卡替尼之间存在协同相互作用。我们注意到，在单独对PRMT5抑制耐药的TNBC细胞系中也可获得协同作用。
总之，我们的数据突出了使用联合策略靶向PRMT5治疗TNBC患者亚群的治疗潜力。
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