靶向PI3K-AKT-mTOR途径是治疗乳腺癌的一种有希望的治疗策略。然而，低响应率和对PI3K-AKT-mTOR抑制剂的耐药性的发展仍然是主要的临床挑战。在这里，我们显示MYC激活驱动了乳腺癌对mTOR抑制剂（mTORi）的耐药性。对小鼠浸润性小叶癌（ILC）肿瘤的多组学分析揭示了在获得对mTORi AZD8055的耐药性的肿瘤中，MYC扩增是重复出现的。MYC激活与与mTORi响应相关的生物学过程有关，并通过促进核糖体蛋白的翻译来抵消mTORi诱导的翻译抑制。在体外和体内诱导MYC可导致小鼠和人类乳腺癌模型的mTORi耐药性。相反，AZD8055耐药的ILC细胞依赖于MYC，这是通过mTORi和MYCi联合治疗的协同效应证明的。值得注意的是，MYC状态与转移性乳腺癌患者对Everolimus治疗的不良反应显著相关。因此，MYC是mTORi耐药的临床相关驱动因素，可能为乳腺癌患者的mTOR靶向治疗分层。©2023年Bhin等。

Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to PI3K-AKT-mTOR inhibitors remain major clinical challenges. Here, we show that MYC activation drives resistance to mTOR inhibitors (mTORi) in breast cancer. Multiomic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent Myc amplifications in tumors that acquired resistance to the mTORi AZD8055. MYC activation was associated with biological processes linked to mTORi response and counteracted mTORi-induced translation inhibition by promoting translation of ribosomal proteins. In vitro and in vivo induction of MYC conferred mTORi resistance in mouse and human breast cancer models. Conversely, AZD8055-resistant ILC cells depended on MYC, as demonstrated by the synergistic effects of mTORi and MYCi combination treatment. Notably, MYC status was significantly associated with poor response to everolimus therapy in metastatic breast cancer patients. Thus, MYC is a clinically relevant driver of mTORi resistance that may stratify breast cancer patients for mTOR-targeted therapies.© 2023 Bhin et al.