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

IF 3.3 4区 医学 Q2 ONCOLOGY
Breast Cancer : Targets and Therapy Pub Date : 2023-11-06 eCollection Date: 2023-01-01 DOI:10.2147/BCTT.S430513
Rayan Dakroub, Solène Huard, Yara Hajj-Younes, Samyuktha Suresh, Bassam Badran, Hussein Fayyad-Kazan, Thierry Dubois
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引用次数: 0

Abstract

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.

靶向PRMT5联合化疗或EGFR/HER2抑制剂治疗三阴性乳腺癌的优势
目的:三阴性乳腺癌(TNBC)是最具侵袭性的乳腺癌亚组,其特点是化疗耐药风险高,复发潜力高。TNBC表现出肿瘤间和肿瘤内的异质性;一半以上表达高EGFR水平,约30%被归类为her2低乳腺癌。高PRMT5 mRNA水平与TNBC的不良预后相关,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PRMT5抑制剂与临床用于治疗TNBC患者的不同化疗药物或fda批准的靶向HER家族成员的抑制剂联合使用的治疗效果。方法:对EPZ015938(一种PRMT5抑制剂,已在临床试验中进行评估)敏感或耐药的TNBC细胞系进行增殖和集落形成试验。分析的化疗药物为顺铂、阿霉素、喜树碱和紫杉醇。试验的靶向治疗方法有厄洛替尼(EGFR抑制剂)、奈拉替尼(EGFR/HER2/HER4抑制剂)和图卡替尼(HER2抑制剂)。结果:我们发现PRMT5抑制主要与顺铂协同作用,与阿霉素或喜树碱协同作用程度较小,但与紫杉醇不协同作用,损害TNBC细胞增殖。PRMT5抑制也与厄洛替尼和奈拉替尼在TNBC细胞系中协同作用,特别是在那些过表达EGFR的细胞系中。此外,在her2低TNBC细胞系和her2阳性乳腺癌细胞系中观察到neratinib和tucatinib的协同相互作用。我们注意到,在单独抵抗PRMT5抑制的TNBC细胞系中可以获得协同作用。结论:总的来说,我们的数据强调了靶向PRMT5使用组合策略治疗TNBC患者亚群的治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
4.10
自引率
0.00%
发文量
40
审稿时长
16 weeks
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