Effects of functional ABCG2 polymorphisms on the sensitivities/adverse effects of gefitinib in patients with non-small-cell lung cancer

ABCG2是一种半大小的atp结合盒转运体，参与细胞吉非替尼转运。据报道，C421A ABCG2基因变异与白人非小细胞肺癌患者吉非替尼诱导的腹泻有关。导致Q141K取代的C421A ABCG2在亚洲人群中更为普遍。因此，我们对75名口服吉非替尼250mg /d治疗的日本非小细胞肺癌患者进行了吉非替尼诱导的不良反应与这种功能多态性之间的推测关系的研究。C376T，导致截断，无功能的ABCG2，也被研究。41例（54.7%）患者至少有一个等位基因携带376T或421A ABCG2，其余34例（45.3%）为ABCG2野生型。在吉非替尼相关腹泻或其他不良反应的发生率方面，组间无显著差异。接下来，建立表达野生型（DLD-1/WT）或141K突变型ABCG2 （DLD-1/Q141K）的DLD-1结肠癌细胞，研究细胞对ABCG2底物药物吉非替尼和SN-38的体外敏感性。ABCG2在DLD-1/Q141K细胞中的表达远低于DLD-1/WT细胞，尽管ABCG2 mRNA水平相似。与DLD-1/Q141K细胞相比，DLD-1/WT细胞获得了更多的SN-38抗性，但与亲代细胞相比，这两种细胞系都没有获得吉非替尼抗性。体外实验数据也表明，ABCG2在吉非替尼的结肠源性细胞毒性中只有有限的作用，而SN-38则没有。

ABCG2 is a half-size ATP-binding cassette transporter implicated in cellular gefitinib transport. Reportedly, the C421A ABCG2 gene variant was associated with gefitinib-induced diarrhea in Caucasian patients with non-small cell lung cancer. C421A ABCG2, resulting in Q141K substitution, is more prevalent in Asian populations. Therefore, the putative relationship between gefitinib-induced adverse effects and this functional polymorphism was investigated in 75 Japanese patients with non-small cell lung cancer treated with gefitinib 250 mg/d orally. C376T, resulting in truncated, non-functional ABCG2, was also investigated. Forty one (54.7%) patients harbored 376T or 421A ABCG2 on at least one allele, while the remaining 34 (45.3%) were wild type for ABCG2. No significant group differences were observed in frequency of gefitinib-related diarrhea or other adverse effects. Next, DLD-1 colon cancer cells expressing wild-type (DLD-1/WT) or 141K mutant ABCG2 (DLD-1/Q141K) were established for investigation of in-vitro cell sensitivity to the ABCG2-substrate drugs, gefitinib and SN-38. ABCG2 expression was much lower in DLD-1/Q141K cells than in DLD-1/WT cells, despite similar ABCG2 mRNA levels. DLD-1/WT cells acquired more resistance to SN-38 than did DLD-1/Q141K cells, but neither cell line acquired gefitinib resistance compared with parental cells. In-vitro data also suggested that ABCG2 has only a limited role in toxicity of gefitinib, but not SN-38, in colon-derived cells.