Molecular target therapy for multidrug-resistant small cell lung cancer

小细胞肺癌（SCLC）是高度恶性的，因为它很容易获得多药耐药。我们已经发现，当SCLC细胞变得多药耐药时，它们的细胞表面上的CD 9和HER 2上调。CD 9诱导SCLC细胞与细胞外基质（ECM）的粘附，通过整合素增强抗凋亡信号导致化学抗性。用阻断抗体或小干扰RNA抑制CD 9诱导化疗耐药SCLC细胞凋亡。另一方面，HER 2抑制剂拉帕替尼通过抑制化疗耐药SCLC细胞上表达的药物外排泵功能来恢复其敏感性。发现这种抑制机制不仅包括直接泵抑制，而且还包括通过HER 2失活介导的Src激活和小窝蛋白-1磷酸化的间接机制。这些结果表明，CD 9和HER 2作为克服SCLC多药耐药的治疗靶点的可能性。

Small cell lung cancer(SCLC) is highly malignant because it easily acquires multidrug resistance. We have found that CD9 and HER2 are upregulated on the cell surface of SCLC cells when they become multidrug-resistant. CD9 induced adhesion of SCLC cells to extracellular matrices(ECM) resulting in chemoresistance by augmenting anti-apoptotic signals via integrins. Inhibition of CD9 with blocking antibody or small interfering RNA induced apoptosis of chemoresistant SCLC cells. On the other hand, HER2 inhibitor lapatinib recovered the sensitivity of chemoresistant SCLC cells by inhibiting the function of drug-efflux pumps expressed on them. This inhibitory mechanism is found to include not only direct pump inhibition but also indirect mechanism through HER2 inactivation-mediated Src activation and caveolin-1 phosphorylation. These findings indicate the possibility of CD9 and HER2 as therapeutic target to overcome multidrug-resistance of SCLC.