Quick Quincy A
Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, USA.
Biomed Rep. 2023 Mar 1;18(4):29. doi: 10.3892/br.2023.1611. eCollection 2023 Apr.
Tyrosine kinase inhibitors are a clinically standard treatment option for non-small cell lung cancers (NSCLCs), the leading cause of cancer-related deaths in the US. These targeted agents include first, second and third generation tyrosine kinase inhibitors; however, these lack clinical efficacy in the treatment of NSCLC due to intrinsic and acquired resistance. This resistance may be a result of genetic aberrations in oncogenic signaling mediators of divergent pathways. The present study aimed to investigate a novel dual tyrosine kinase and PI3K inhibitor, PP121, as a targeted agent in NSCLC cell lines. The present study co-cultured PP121 with healthy human astrocytes, a prevalent cell type located in the brain of NSCLC brain metastases. To date, few preclinical studies have examined the efficacy of PP121 as an anticancer agent, and to the best of my knowledge, no previous studies have previously evaluated its therapeutic potential in the treatment of NSCLC. To investigate the clinical heterogeneity of NSCLC, patient-derived adenocarcinoma (ADC) and squamous cell carcinoma (SCC) xenograft models were used, which exhibited epidermal growth factor receptor (EGFR) mutations and mesenchymal-epithelial transition (MET) factor amplifications. Notably, both EGFR and MET are known contributors to tyrosine kinase inhibitor resistance; thus, the aforementioned mutations and amplifications enabled the effects of PP121 to be evaluated in these solid tumors. In addition, a co-cultured model system using both NSCLC cells and astrocytes was employed to assess the effects of PP121 on the invasion of ADC and SCC cells in a multicellular environment. Results of the present study demonstrated that PP121 exerted an antitumorigenic effect in the aforementioned model systems via downregulation of pharmacodynamic targets.
酪氨酸激酶抑制剂是美国非小细胞肺癌（NSCLC）的临床标准治疗选择，NSCLC是癌症相关死亡的主要原因。这些靶向药物包括第一代、第二代和第三代酪氨酸激酶抑制剂；然而，由于内在和获得性耐药，这些药物在NSCLC治疗中缺乏临床疗效。这种耐药可能是不同途径的致癌信号介质中基因畸变的结果。本研究旨在研究一种新型双酪氨酸激酶和PI3K抑制剂PP121作为NSCLC细胞系中的靶向药物。本研究将PP121与健康人星形胶质细胞共同培养，星形胶质细胞是NSCLC脑转移瘤脑中普遍存在的细胞类型。迄今为止，很少有临床前研究检测PP121作为抗癌药物的疗效，据我所知，以前没有研究评估过其在NSCLC治疗中的治疗潜力。为了研究NSCLC的临床异质性，使用了患者来源的腺癌（ADC）和鳞状细胞癌（SCC）异种移植模型，这些模型表现出表皮生长因子受体（EGFR）突变和间充质-上皮转化（MET）因子扩增。值得注意的是，EGFR和MET都是已知的酪氨酸激酶抑制剂耐药的促成因素；因此，上述突变和扩增使得能够在这些实体瘤中评估PP121的作用。此外，采用一种使用NSCLC细胞和星形胶质细胞的共培养模型系统来评估PP121在多细胞环境中对ADC和SCC细胞侵袭的影响。本研究结果表明，PP121通过下调药效学靶点在上述模型系统中发挥抗肿瘤作用。
