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.
酪氨酸激酶抑制剂（TKIs）对非小细胞肺癌（NSCLC）多药耐药性（MDR）的影响是癌症治疗的关键问题。虽然TKIs能有效靶向癌细胞的特异性信号通路，但它们也可能作为ABC转运蛋白的底物，从而可能引发MDR。本研究旨在评估17例患者来源的NSCLC培养物对10种常用TKIs的反应，并将这些反应与患者的突变谱相关联。通过体外免疫荧光检测，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，以建立功能性诊断方法。NSCLC培养物对TKIs的反应存在差异，其中厄洛替尼无论突变负荷或EGFR状态如何均表现出良好疗效。然而，厄洛替尼对MDR机制的调控（如增加ABCG2表达）突显了其治疗相关的挑战。其他TKIs疗效有限，反映了NSCLC治疗反应的变异性。与药物耐药性和敏感性相关的信号通路基因改变（包括TP53突变）可能是导致TKIs反应差异的原因。ABC转运蛋白表达、基因改变与TKIs反应之间的关系未呈现一致模式。我们的结果表明，除突变状态外，进行功能性敏感性筛查对于确定合适的TKIs治疗策略至关重要。这些发现强调了在优化NSCLC治疗时，需综合考虑药物敏感性、脱靶效应、MDR风险及患者特异性基因谱的重要性，并凸显了个体化治疗策略（尤其在早期阶段）的潜力。
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