State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China.
Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, P. R. China.
Cell Death Dis. 2019 Aug 13;10(8):615. doi: 10.1038/s41419-019-1844-2.
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Development of novel chemotherapeutics is still required to enable successful treatment and improve survival for CRC patients. Here, we found that osimertinib (OSI) exhibits potent anti-CRC effects by inducing apoptosis, independent of its selective inhibitory activity targeting the EGFR T790M mutation. Intriguingly, OSI treatment triggers autophagic flux in CRC cells. Inhibition of autophagy markedly augments OSI-induced apoptosis and growth inhibition in CRC cells, suggesting a protective role of autophagy in response to OSI treatment. Mechanistically, OSI upregulates the expression of monocarboxylate transporter 1 (MCT1) and subsequently activates LKB1/AMPK signaling, leading to autophagy induction in CRC cells. Notably, OSI significantly exaggerates the sensitivity of CRC cells to the first-line drugs 5-fluorouracil or oxaliplatin. Taken together, our study unravels a novel mechanism of OSI-mediated protective autophagy involving MCT1/LKB1/AMPK signaling, and suggests the use of OSI as a potential agent for clinical CRC treatment.
结直肠癌（CRC）是全球最常见的癌症之一。为了使 CRC 患者的治疗取得成功并提高其生存率，仍然需要开发新的化疗药物。在这里，我们发现奥希替尼（OSI）通过诱导细胞凋亡发挥强大的抗 CRC 作用，而不依赖于其针对 EGFR T790M 突变的选择性抑制活性。有趣的是，OSI 治疗可触发 CRC 细胞中的自噬流。自噬的抑制显著增强了 OSI 诱导的 CRC 细胞中的细胞凋亡和生长抑制，表明自噬在 OSI 治疗中起保护作用。从机制上讲，OSI 上调单羧酸转运蛋白 1（MCT1）的表达，随后激活 LKB1/AMPK 信号通路，导致 CRC 细胞中的自噬诱导。值得注意的是，OSI 显著增加了 CRC 细胞对一线药物 5-氟尿嘧啶或奥沙利铂的敏感性。综上所述，我们的研究揭示了 OSI 介导的涉及 MCT1/LKB1/AMPK 信号通路的保护性自噬的新机制，并表明将 OSI 用作临床 CRC 治疗的潜在药物。
