Laboratory of Molecular Pharmacology, Department of Experimental Oncology, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.
J Exp Clin Cancer Res. 2024 Jan 2;43(1):6. doi: 10.1186/s13046-023-02933-5.
About 10% of NSCLCs are mutated in KRAS and impaired in STK11/LKB1, a genetic background associated with poor prognosis, caused by an increase in metastatic burden and resistance to standard therapy. LKB1 is a protein involved in a number of biological processes and is particularly important for its role in the regulation of cell metabolism. LKB1 alterations lead to protein loss that causes mitochondria and metabolic dysfunction that makes cells unable to respond to metabolic stress. Different studies have shown how it is possible to interfere with cancer metabolism using metformin and caloric restriction (CR) and both modify the tumor microenvironment (TME), stimulating the switch from "cold" to "hot". Given the poor therapeutic response of KRAS/LKB1 patients, and the role of LKB1 in cell metabolism, we examined whether the addition of metformin and CR enhanced the response to chemo or chemo-immunotherapy in LKB1 impaired tumors.
Mouse cell lines were derived from lung nodules of transgenic mice carrying KRAS with either functional LKB1 (KRAS/LKB1) or mutated LKB1 (KRAS/LKB1). Once stabilized in vitro, these cell lines were inoculated subcutaneously and intramuscularly into immunocompetent mice. Additionally, a patient-derived xenograft (PDX) model was established by directly implanting tumor fragments from patient into immunocompromised mice. The mice bearing these tumor models were subjected to treatment with chemotherapy or chemo-immunotherapy, both as standalone regimens and in combination with metformin and CR.
Our preclinical results indicate that in NSCLC KRAS/LKB1 tumors, metformin and CR do enhance the response to chemo and chemo-immunotherapy, inducing a metabolic stress condition that these tumors are not able to overcome. Analysis of immune infiltrating cells did not bring to light any strong correlation between the TME immune-modulation and the tumor response to metformin and CR.
Our in vitro and in vivo preliminary studies confirm our hypothesis that the addition of metformin and CR is able to improve the antitumor activity of chemo and chemoimmunotherapy in LKB1 impaired tumors, exploiting their inability to overcome metabolic stress.
大约 10%的 NSCLC 存在 KRAS 突变和 STK11/LKB1 缺陷，这是一种预后不良的遗传背景，其原因是转移负担增加和对标准治疗的耐药性。LKB1 是一种参与多种生物学过程的蛋白质，特别是在调节细胞代谢方面发挥着重要作用。LKB1 的改变导致蛋白质丢失，从而导致线粒体和代谢功能障碍，使细胞无法应对代谢应激。不同的研究表明，使用二甲双胍和热量限制（CR）来干扰癌症代谢是可行的，这两种方法都可以改变肿瘤微环境（TME），刺激从“冷”到“热”的转变。鉴于 KRAS/LKB1 患者的治疗反应较差，以及 LKB1 在细胞代谢中的作用，我们研究了在 LKB1 缺陷肿瘤中添加二甲双胍和 CR 是否增强了对化疗或化疗免疫治疗的反应。
从小鼠携带 KRAS 的肺结节中分离出 KRAS 与功能性 LKB1（KRAS/LKB1）或突变 LKB1（KRAS/LKB1）的小鼠细胞系。在体外稳定后，将这些细胞系皮下和肌肉内接种到免疫功能正常的小鼠中。此外，通过直接将来自患者的肿瘤碎片植入免疫缺陷小鼠中建立了患者来源的异种移植（PDX）模型。将这些肿瘤模型的小鼠进行化疗或化疗免疫治疗，既作为单独的方案，也与二甲双胍和 CR 联合使用。
我们的临床前研究结果表明，在 NSCLC KRAS/LKB1 肿瘤中，二甲双胍和 CR 确实增强了对化疗和化疗免疫治疗的反应，诱导了这些肿瘤无法克服的代谢应激状态。对免疫浸润细胞的分析并没有揭示出 TME 免疫调节与二甲双胍和 CR 对肿瘤的反应之间有任何强烈的相关性。
我们的体外和体内初步研究证实了我们的假设，即添加二甲双胍和 CR 能够改善 LKB1 缺陷肿瘤对化疗和化疗免疫治疗的抗肿瘤活性，利用其无法克服代谢应激的能力。
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