Mekonnen Negesse, Yang Hobin, Rajasekaran Nirmal, Song Kyoung, Choi Yoon-La, Shin Young Kee
Research Institute of Pharmaceutical Science, Department of Pharmacy, Seoul National University, College of Pharmacy, Seoul, South Korea; Department of Veterinary Science, School of Animal Science and Veterinary Medicine, Bahir Dar University, Bahir Dar, Ethiopia.
College of Pharmacy, Kyungsung University, Busan, South Korea.
Transl Oncol. 2025 Jan;51:102204. doi: 10.1016/j.tranon.2024.102204. Epub 2024 Dec 3.
MYC amplification is disproportionally elevated in triple-negative breast cancer (TNBC) compared to other subtypes of breast cancer. Indeed, MYC has long been considered an undruggable oncogene using conventional drug design strategies or small molecules. We hypothesized that targeting MYC using asymmetric siRNA (asiRNA) alone or in combination with chemotherapeutic agents or indirectly via BRD4 and RRM2, may curb its oncogenic behavior. We developed paclitaxel-, doxorubicin-, and cisplatin-resistant MDA-MB-231 cells to study MYC's role in upregulating DNA repair genes during drug resistance development. Our results showed that the knockdown of either MYC or RRM2 downregulated both RAD51 and PARP1 but increased γH2AX. The cytotoxic effect of RRM2 knockdown was significantly (p < 0.05) higher than that of direct MYC knockdown. The knockdown of BRD4 was more effective than the direct knockdown of MYC in downregulating MYC protein. The combined use of asiRNA-VP (Vinylphosphonate) with dacomitinib or talazoparib was synthetic lethal in TNBC cell lines. Compared to chemotherapy-sensitive cells, resistant cells showed overexpression of MYC, RRM2, RAD51, and PARP1 proteins upon chemotherapy treatment, but downregulated in cells treated with asiRNA-VP combination. We confirmed that MYC knockdown upregulated cFLIP, BCL2, STAT1, pSTAT1, STAT2, and cleaved saspase-3 in both TNBC and non-small cell lung cancer (NSCLC) cell lines. Finally, we recommend a combination treatment approach that synergizes with MYC inhibition rather than monotherapy or indirect targeting via upstream regulators such as the BRD4 and RRM2 genes or selective modulation at the protein level to suppress anti-apoptotic genes (cFLIP and BCL2) at the same time.
与其他乳腺癌亚型相比，三阴性乳腺癌（TNBC）中MYC扩增水平异常升高。事实上，长期以来，使用传统药物设计策略或小分子药物，MYC一直被认为是一种难以靶向的致癌基因。我们推测，单独使用不对称小干扰RNA（asiRNA）或与化疗药物联合使用，或通过BRD4和RRM2间接靶向MYC，可能会抑制其致癌行为。我们构建了对紫杉醇、阿霉素和顺铂耐药的MDA-MB-231细胞，以研究MYC在耐药形成过程中上调DNA修复基因的作用。我们的结果表明，敲低MYC或RRM2均可下调RAD51和PARP1表达，但增加γH2AX表达。敲低RRM2的细胞毒性作用显著高于直接敲低MYC（p<0.05）。敲低BRD4比直接敲低MYC更有效地下调MYC蛋白表达。在TNBC细胞系中，asiRNA-VP（乙烯基膦酸酯）与达可替尼或他拉唑帕尼联合使用具有合成致死性。与化疗敏感细胞相比，耐药细胞在化疗处理后显示MYC、RRM2、RAD51和PARP1蛋白过表达，但在用asiRNA-VP联合处理的细胞中表达下调。我们证实，敲低MYC可上调TNBC和非小细胞肺癌（NSCLC）细胞系中的cFLIP、BCL2、STAT1、pSTAT1、STAT2和裂解的半胱天冬酶-3。最后，我们推荐一种联合治疗方法，该方法与MYC抑制协同作用，而不是单一疗法或通过BRD4和RRM2基因等上游调节因子进行间接靶向，或在蛋白质水平进行选择性调节，以同时抑制抗凋亡基因（cFLIP和BCL2）。
