LBPO.ET02 · 实验与分子治疗 · Late-Breaking
靶向剪接体蛋白hnRNPH1/H2的治疗在BRAF抑制剂耐药性黑色素瘤中展现出强效抗黑色素瘤活性并增强肿瘤免疫应答
Therapeutic Targeting of Spliceosomal Proteins hnRNPH1/H2 Demonstrates Potent Anti-Melanoma Activity In BRAF Inhibitor Resistant Melanoma, and Enhances Tumor Immune Response
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摘要 Abstract
中文摘要
背景：黑色素瘤仍是最具侵袭性的恶性肿瘤之一，对BRAF抑制剂等靶向治疗的耐药性持续限制着患者的长期预后。我们此前鉴定出小分子化合物2155-14和2155-18，它们通过下调剪接体蛋白hnRNPH1和H2抑制黑色素瘤生长。
方法：在雄性和雌性Balb/C小鼠中评估急性毒性，皮下给予每种化合物50 mg/kg/天，持续21天。评估临床行为、体重、血液学、血液生化和器官形态。在裸鼠中，以25 mg/kg的2155-14或2155-18每周三次治疗BRAF抑制剂敏感型和BRAF/NRAS抑制剂耐药型A375黑色素瘤异种移植瘤，与vemurafenib单药以及vemurafenib/cobimetinib联合治疗进行比较，评估抗肿瘤疗效。在免疫功能健全的B16F10荷瘤同系小鼠模型中评估免疫调节效应。
结果：治疗小鼠未检测到显著毒性，表明具有良好的短期安全性。在A375异种移植瘤中，包括BRAF抑制剂敏感型和BRAF/NRAS抑制剂耐药型模型，两种化合物均显著减少肿瘤生长，疗效与单药治疗以及vemurafenib/cobimetinib联合治疗相当。肿瘤体积、肿瘤重量和组织病理学证实了对肿瘤进展的强效抑制。在B16F10模型中，任一化合物治疗均增加了肿瘤微环境内多种免疫细胞群的浸润，表明抗肿瘤免疫激活增强。
结论：化合物2155-14和2155-18表现出强效的临床前抗肿瘤活性、极小的毒性以及免疫参与的证据。这些发现支持hnRNPH1/H2剪接体蛋白调节作为治疗晚期或耐药性黑色素瘤的一种有前景的治疗方法，并为未来的开发（如单药治疗或与免疫治疗联合）提供了理论依据。
关键词：黑色素瘤，剪接体蛋白，BRAF和NRAS抑制剂耐药，异种移植模型，细胞系异种移植，免疫治疗
查看英文原文 English abstract
Background: Melanoma remains one of the most aggressive malignancies, and resistance to targeted therapies such as BRAF inhibitors continues to limit long-term patient outcomes. We previously identified small molecule compounds, 2155-14 and 2155-18, that inhibit melanoma growth by downregulating spliceosomal proteins hnRNPH1 and H2.
Methods: Acute toxicity was evaluated in male and female Balb/C mice treated subcutaneously with 50 mg/kg/day of each compound for 21 days. Clinical behavior, body weight, hematology, blood chemistry, and organ morphology were assessed. Antitumor efficacy was examined in both BRAF inhibitor-sensitive and BRAF/NRAS inhibitor-resistant A375 melanoma xenografts in nude athymic mice treated with 25 mg/kg of 2155-14 or 2155-18 three times weekly, compared with vemurafenib monotherapy and vemurafenib/cobimetinib combination. Immunomodulatory effects were evaluated in an immunocompetent B16F10 melanoma-bearing syngeneic mouse model.
Results: No significant toxicities were detected in treated mice, demonstrating a favorable short-term safety profile. In A375 xenografts, including the BRAF inhibitor-sensitive and BRAF/NRAS inhibitor-resistant models, both compounds significantly reduced tumor growth, with efficacy comparable to monotherapy and the vemurafenib/cobimetinib combination. Tumor volume, tumor weight, and histopathology confirmed robust inhibition of tumor progression. In the B16F10 model, treatment with either compound increased infiltration of multiple immune cell populations within the tumor microenvironment, indicating enhanced antitumor immune activation.
Conclusions: Compounds 2155-14 and 2155-18 exhibit strong preclinical anti-tumor activity, minimal toxicity, and evidence of immune engagement. These findings support hnRNPH1/H2 spliceosomal protein modulation as a promising therapeutic approach for advanced or drug-resistant melanoma and provide a rationale for future development, such as monotherapy or in combination with immunotherapy.
Keywords: Melanoma, Spliceosomal proteins, BRAF and NRAS inhibitor resistance, Xenograft models, cell line xenograft, immunotherapy
利益披露 Disclosure
S. Velayutham, None..
M. Sultan, None..
T. Desai, None..
S. Shah, None..
N. Nguyen, None..
E. Rome, None..
R. Seerattan, None..
A. Singh, None..
K. Smalley, None..
J. Choi, None..
V. Beljanski, None..
D. Minond, None.