蛋白激酶D1抑制EMT逆转肺腺癌EGFR-TKIs获得性耐药的作用机制研究

Acquired resistance to EGFR-TKIs after initial clinical benefit inevitably occurs in most EGFR mutant lung adenocarcinoma patients. EMT functions as one of the most critical mechanisms of TKIs acquired resistance. However, the role of protein kinase D1(PKD1) which is determined as a novel regulator of EMT in TKIs acquired resistance is still unknown. We reported that PKD1 is downregulated and functions as a tumor suppressor in non-small cell lung cancer. In addition, our preliminary results showed that constituvely active PKD1 reduced the EMT of lung adenocarcinooma cells. Therefore we hypothesize that PKD1 plays an important role in TKIs acquired resistance by inhibiting EMT, and upregulation or activation of PKD1 will effectively reverse drug resistance. To test the hypothesis, we will explore the role and mechanism of PKD1 in lung adenocarcinoma TKIs acquired resistance in TKIs acquired resistant lung cancer cells, animal models and cancer tissues. This study will provide a sound theoretical basis and a novel way for the research and therapy of TKIs acquired resistance.

EGFR突变的肺腺癌在TKIs治疗过程中发生获得性耐药是目前肺癌靶向治疗中一个亟待解决的问题。上皮间质转化（EMT）是TKIs获得性耐药发生的重要机制之一。蛋白激酶D1（PKD1）作为EMT新的调控因子，在TKIs获得性耐药中的作用尚不清楚。我们的前期研究发现，PKD1抑制多条肿瘤相关信号通路，在非小细胞肺癌中发挥抑癌作用，PKD1的激活能抑制肺腺癌细胞EMT发生。因此我们假设：PKD1通过抑制EMT在逆转肺腺癌TKIs获得性耐药中发挥作用。为验证该假说，我们将在TKIs获得性耐药肺腺癌细胞中特异性上调或敲除PKD1，探讨PKD1对耐药细胞EMT及逆转TKIs获得性耐药的作用和机制，并在动物模型和临床肿瘤标本中进一步验证PKD1与TKIs获得性耐药的关系。本研究将从PKD1这个新视点为揭示TKIs获得性耐药的发生机制奠定理论基础，为肺腺癌的靶向治疗提供新的研究思路。

肺癌已成为我国乃至世界范围恶性肿瘤死亡的首要原因。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）能有效改善敏感突变人群的无进展生存期和生活质量，并具有良好的安全性。然而，大部分对EGFR-TKIs 敏感的肺腺癌患者在治疗一段时间后最终发生获得性耐药，使得TKIs治疗的中位有效时间仅为8～10 个月。因此，克服TKIs获得性耐药是肺癌治疗亟待解决的问题。本课题研究发现PKD1在耐药肺癌组织中高表达，下调PKD1可显著抑制耐药细胞增殖，并下调p-S6K1、p-S6、p-ERK及p-AKT水平。在发生TKIs耐药的临床患者中，热消融联合TKIs相较于全身化疗能更好的延长患者无进展生存期（PFS）及总生存期（OS），且副作用小耐受性好。但热消融有升高患者VEGF、MMP-9进而刺激肿瘤发生EMT的潜在作用，我们的研究显示微波消融联合抗血管生成药物能有效逆转EMT，提高局部疗效并改善远处转移。因此，PKD1抑制剂、抗血管生成药物及热消融的联合治疗将成为TKIs获得性耐药非小细胞肺癌治疗的新模式。