PDF(Pubmed)
Abstract：
The impact of tyrosine kinase inhibitors (TKIs) on multidrug resistance (MDR) in non-small cell lung carcinoma (NSCLC) is a critical aspect of cancer therapy. While TKIs effectively target specific signaling pathways of cancer cells, they can also act as substrates for ABC transporters, potentially triggering MDR. The aim of our study was to evaluate the response of 17 patient-derived NSCLC cultures to 10 commonly prescribed TKIs and to correlate these responses with patient mutational profiles. Using an ex vivo immunofluorescence assay, we analyzed the expression of the MDR markers ABCB1, ABCC1, and ABCG2, and correlated these data with the genetic profiles of patients for a functional diagnostic approach. NSCLC cultures responded differently to TKIs, with erlotinib showing good efficacy regardless of mutation burden or EGFR status. However, the modulation of MDR mechanisms by erlotinib, such as increased ABCG2 expression, highlights the challenges associated with erlotinib treatment. Other TKIs showed limited efficacy, highlighting the variability of response in NSCLC. Genetic alterations in signaling pathways associated with drug resistance and sensitivity, including TP53 mutations, likely contributed to the variable responses to TKIs. The relationships between ABC transporter expression, gene alterations, and response to TKIs did not show consistent patterns. Our results suggest that in addition to mutational status, performing functional sensitivity screening is critical for identifying appropriate treatment strategies with TKIs. These results underscore the importance of considering drug sensitivity, off-target effects, MDR risks, and patient-specific genetic profiles when optimizing NSCLC treatment and highlight the potential for personalized approaches, especially in early stages.
摘要：
酪氨酸激酶抑制剂（TKIs）对非小细胞肺癌（NSCLC）多药耐药（MDR）的影响是癌症治疗的关键方面。虽然TKIs有效地靶向癌细胞的特定信号通路，它们也可以作为ABC运输者的底物，可能触发MDR。我们研究的目的是评估17个患者来源的NSCLC培养物对10个常用处方的TKI的反应，并将这些反应与患者突变谱相关联。使用离体免疫荧光测定法，我们分析了MDR标志物ABCB1,ABCC1和ABCG2的表达,并将这些数据与患者的基因谱进行关联,以进行功能性诊断.NSCLC文化对TKIs的反应不同，无论突变负荷或EGFR状态如何，厄洛替尼都显示出良好的疗效。然而,厄洛替尼对MDR机制的调节，如ABCG2表达增加，强调与厄洛替尼治疗相关的挑战.其他TKIs疗效有限，强调非小细胞肺癌反应的变异性。与耐药性和敏感性相关的信号通路的遗传改变，包括TP53突变，可能是对TKIs的变量反应的原因。ABC转运体表达之间的关系，基因改变，对TKIs的反应没有显示出一致的模式。我们的结果表明，除了突变状态，进行功能敏感性筛查对于确定合适的TKIs治疗策略至关重要.这些结果强调了考虑药物敏感性的重要性，脱靶效应,MDR风险，以及优化NSCLC治疗时的患者特异性基因谱，并突出个性化方法的潜力，尤其是在早期阶段。
