State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, P.R. China.
College of Biological and Pharmaceutical Engineering, West Anhui University, Lu'an, 237012, China.
Cell Death Dis. 2024 Sep 30;15(9):704. doi: 10.1038/s41419-024-07082-x.
Repositioning approved antitumor drugs for different cancers is a cost-effective approach. Gilteritinib was FDA-approved for the treatment of FLT3-mutated acute myeloid leukemia in 2018. However, the therapeutic effects and mechanism of Gilteritinib on other malignancies remain to be defined. In this study, we identified that gilteritinib has an inhibitory effect on lung cancer cells (LCCs) without FLT3 mutation in vitro and in vivo. Unexpectedly, we found that gilteritinib induces cholesterol accumulation in LCCs via upregulating cholesterol biosynthetic genes and inhibiting cholesterol efflux. This gilteritinib-induced cholesterol accumulation not only attenuates the antitumor effect of gilteritinib but also induces gilteritinib-resistance in LCCs. However, when cholesterol synthesis was prevented by squalene epoxidase (SQLE) inhibitor NB-598, both LCCs and gilteritinib-resistant LCCs became sensitive to gilteritinib. More importantly, the natural cholesterol inhibitor 25-hydroxycholesterol (25HC) can suppress cholesterol biosynthesis and increase cholesterol efflux in LCCs. Consequently, 25HC treatment significantly increases the cytotoxicity of gilteritinib on LCCs, which can be rescued by the addition of exogenous cholesterol. In a xenograft model, the combination of gilteritinib and 25HC showed significantly better efficacy than either monotherapy in suppressing lung cancer growth, without obvious general toxicity. Thus, our findings identify an increase in cholesterol induced by gilteritinib as a mechanism for LCC survival, and highlight the potential of combining gilteritinib with cholesterol-lowering drugs to treat lung cancer.
重新定位已批准的抗肿瘤药物用于治疗不同癌症是一种具有成本效益的方法。Gilteritinib 于 2018 年被 FDA 批准用于治疗 FLT3 突变型急性髓系白血病。然而，Gilteritinib 对其他恶性肿瘤的治疗效果和机制仍有待确定。在这项研究中，我们发现在体外和体内，Gilteritinib 对没有 FLT3 突变的肺癌细胞（LCCs）具有抑制作用。出乎意料的是，我们发现 Gilteritinib 通过上调胆固醇生物合成基因和抑制胆固醇外排来诱导 LCCs 中的胆固醇积累。这种 Gilteritinib 诱导的胆固醇积累不仅减弱了 Gilteritinib 的抗肿瘤作用，而且还诱导了 LCCs 对 Gilteritinib 的耐药性。然而，当胆固醇合成被 squalene epoxidase (SQLE) 抑制剂 NB-598 阻止时，LCCs 和 Gilteritinib 耐药的 LCCs 对 Gilteritinib 变得敏感。更重要的是，天然胆固醇抑制剂 25-羟胆固醇（25HC）可以抑制 LCCs 中的胆固醇生物合成并增加胆固醇外排。因此，25HC 处理显著增加了 Gilteritinib 对 LCCs 的细胞毒性，外源性胆固醇的添加可以挽救这种作用。在异种移植模型中，与单独使用 Gilteritinib 相比，Gilteritinib 和 25HC 的联合使用在抑制肺癌生长方面显示出更好的疗效，而没有明显的全身毒性。因此，我们的研究结果确定了 Gilteritinib 诱导的胆固醇增加是 LCC 存活的一种机制，并强调了将 Gilteritinib 与降低胆固醇药物联合用于治疗肺癌的潜力。
