Colorectal cancer is the third most frequently diagnosed malignancies among both men and women, which has an increased mortality but a poor prognosis. Targeting mTOR becomes an effective approach that shows promising antitumor activities in various cancers including colonic carcinoma. However, the potential mechanism against colon cancer remains incompletely understood. Here, we demonstrated that the anti-cancer effect of AZD8055 and OSI-027 is at least in part modulated by the gradual process of apoptosis initiation, progressing from mTOR suppression, 4EBP1 dephosphorylation, or EZH2 suppression, thereby leading to PUMA-dependent apoptosis via the intrinsic mitochondrial pathway. Furthermore, AZD8055 inhibited colorectal cancer tumor growth in mice significantly. PUMA deletion caused resistance of dual mTOR inhibitors, suggesting PUMA mediated carcinogenesis in vitro and in vivo. Collectively, these findings established a vital status of PUMA in driving the antineoplastic efficacy of targeting mTOR by AZD8055 and OSI-027 and offered the rationales for the current clinical assessment.

结直肠癌是男性和女性中第三大最常被诊断出的恶性肿瘤，其死亡率增加但预后较差。靶向 mTOR 成为一种有效的方法，在包括结肠癌在内的各种癌症中显示出有希望的抗肿瘤活性。然而，对抗结肠癌的潜在机制仍不完全清楚。在这里，我们证明了 AZD8055 和 OSI-027 的抗癌作用至少部分受到细胞凋亡起始的逐渐过程的调节，从 mTOR 抑制、4EBP1 去磷酸化或 EZH2 抑制进展，从而导致 PUMA 依赖性细胞凋亡通过内在的线粒体途径。此外，AZD8055 显着抑制小鼠结直肠癌肿瘤的生长。PUMA 缺失导致双重 mTOR 抑制剂的耐药性，提示 PUMA 在体外和体内介导致癌作用。总的来说，这些发现确立了 PUMA 在推动 AZD8055 和 OSI-027 靶向 mTOR 的抗肿瘤疗效方面的重要地位，并为当前的临床评估提供了依据。