Molecular target therapy for multidrug-resistant small cell lung cancer

小细胞肺癌（Small cell lung cancer， SCLC）因其易产生多药耐药而具有高度恶性。我们发现，当SCLC细胞产生多药耐药时，细胞表面的CD9和HER2表达上调。CD9通过整合素增强抗凋亡信号，诱导SCLC细胞粘附于细胞外基质（ECM），导致化疗耐药。阻断抗体或小干扰RNA抑制CD9诱导化疗耐药SCLC细胞凋亡。另一方面，HER2抑制剂拉帕替尼通过抑制SCLC上表达的药物外排泵的功能，恢复了SCLC耐药细胞的敏感性。这种抑制机制不仅包括直接的泵抑制，还包括通过HER2失活介导的Src激活和caveolin-1磷酸化的间接机制。这些发现提示CD9和HER2有可能成为克服SCLC多药耐药的治疗靶点。

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.