Overexpression of MYC oncogene is highly prevalent in many malignancies such as aggressive triple-negative breast cancers (TNBCs) and it is associated with very poor outcome. Despite decades of research, attempts to effectively inhibit MYC, particularly with small molecules, still remain challenging due to the featureless nature of its protein structure. Herein, we describe the engineering of the dominant-negative MYC peptide (OmoMYC) linked to a functional penetrating 'Phylomer' peptide (FPPa) as a therapeutic strategy to inhibit MYC in TNBC. We found FPPa-OmoMYC to be a potent inducer of apoptosis (with IC₅₀ from 1-2 µM) in TNBC cells with negligible effects in non-tumorigenic cells. Transcriptome analysis of FPPa-OmoMYC-treated cells indicated that the fusion protein inhibited MYC-dependent networks, inducing dynamic changes in transcriptional, metabolic, and apoptotic processes. We demonstrated the efficacy of FPPa-OmoMYC in inhibiting breast cancer growth when injected orthotopically in TNBC allografts. Lastly, we identified strong pharmacological synergisms between FPPa-OmoMYC and chemotherapeutic agents. This study highlights a novel therapeutic approach to target highly aggressive and chemoresistant MYC-activated cancers.

中文翻译：

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抑制MYC的肿瘤穿透肽作为三阴性乳腺癌的有效靶向治疗策略。

MYC癌基因的过度表达在许多恶性肿瘤（例如侵袭性三阴性乳腺癌（TNBCs））中非常普遍，并且与非常差的预后相关。尽管进行了数十年的研究，但由于其蛋白质结构无特征的特性，有效抑制MYC的尝试（尤其是使用小分子的MYC）仍然具有挑战性。在本文中，我们描述了与功能性穿透性“ Phylomer”肽（FPPa）连接的显性负性MYC肽（OmoMYC）的工程设计，作为抑制TNBC中MYC的治疗策略。我们发现FPPa-OmoMYC是有效的细胞凋亡诱导剂（IC ₅₀浓度为1-2 µM（在TNBC细胞中），而在非致瘤细胞中的影响可忽略不计。FPPa-OmoMYC处理的细胞的转录组分析表明，融合蛋白抑制MYC依赖性网络，诱导转录，代谢和凋亡过程的动态变化。当在原位移植到TNBC同种异体移植物中时，我们证明了FPPa-OmoMYC抑制乳腺癌生长的功效。最后，我们确定了FPPa-OmoMYC与化学治疗剂之间的强药理协同作用。这项研究突出了针对高侵袭性和化学耐药性MYC激活的癌症的新型治疗方法。