肺癌是世界上最常见的癌症之一。化疗是标准的临床治疗方法。然而，肿瘤细胞常常在化疗后产生多药耐药性，这是癌症治疗中不可避免的瓶颈。因此，本研究使用了吉西他滨耐药（GEM-R）CL1-0肺癌细胞。首先，我们使用流式细胞术和Western印迹分析检查耐药和母源细胞之间的差异表现。结果显示，与母源细胞相比，GEM-R CL1-0细胞明显增强了AKT通路的激活，促进了生存和生长，并减少了活性氧物种-外周信号调控激酶（ROS-ERK）通路的激活。接下来，在一个异种移植模型中进一步研究了AKT和ERK通路在肿瘤生长中的作用。结果显示，增强AKT并抑制ERK的激活可减少对GEM抑制肿瘤生长的影响。最后，结合以上结果，我们发现GEM-R CL1-0细胞通过激活磷脂酰肌醇3-激酶/AKT/NF-kB通路和抑制ROS-ERK通路，降低了对GEM的敏感性，从而产生了GEM的耐药性。因此，AKT和ERK通路是提高癌细胞对抗癌药物敏感性的潜在靶点。© 2023 Wiley Periodicals LLC.

Lung cancer is one of the most common cancers in the world. Chemotherapy is a standard clinical treatment. However, tumor cells often develop multidrug resistance after chemotherapy, an inevitable bottleneck in cancer treatment. Therefore, this study used gemcitabine-resistant (GEM-R) CL1-0 lung cancer cells. First, we used flow cytometry and western blot analysis to examine differences in performance between resistant and parental cells. The results showed that compared with parental cells, GEM-R CL1-0 cells significantly enhanced the activation of the AKT pathway, which promoted survival and growth, and decreased the activation of the reactive oxygen species-extracellular signal-regulated kinase (ROS)-ERK pathway. Next, the AKT and ERK pathways' role in tumor growth was further explored in vivo using a xenograft model. The results showed that enhancing AKT and inhibiting ERK activation reduced GEM-induced inhibition of tumor growth. Finally, combining the above results, we found that GEM-R CL1-0 cells showed reduced sensitivity to GEM by activating the phosphatidylinositol 3-kinase/AKT/NF-kB pathway and inhibiting the ROS-ERK pathway leading to resistance against GEM. Therefore, the AKT and ERK pathways are potential targets for improving the sensitivity of cancer cells to anticancer drugs.© 2023 Wiley Periodicals LLC.