Webber Philip J, Park Chanhee, Qui Min, Ramalingam Suresh S, Khuri Fadlo R, Fu Haian, Du Yuhong
Department of Pharmacology, Emory University, Atlanta, GA, USA.
Emory Chemical Biology Discovery Center, Emory University School of Medicine, Emory University, Atlanta, GA, USA.
Oncoscience. 2015 Sep 15;2(9):765-776. doi: 10.18632/oncoscience.245. eCollection 2015.
Discovery of effective drug combinations is a promising strategy to improve patient survival. This study explores the impact of heat shock protein 90 (Hsp90) inhibition in combination with focal adhesion kinase (FAK) inhibitor on the growth of non-small cell lung cancer cells (NSCLC cells). Our data show that 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG), a well-studied Hsp90 inhibitor, synergized with FAK inhibitor, PF-573228, on the growth inhibition of NSCLC cells. This combination effect was confirmed using additional chemically distinct Hsp90 inhibitor, STA-9090, which is currently undergoing phase 3 clinical evaluation. Co-treatment of NSCLC cells with Hsp90 and FAK inhibitors significantly enhanced the inhibition on long-term colony formation compared to that with single agent. Inhibition of FAK exacerbated the G2 cell cycle arrest and annexin-V apoptotic staining induced by 17-AAG. Further mechanistic studies revealed that the combination of Hsp90 and FAK inhibitors reduced the activity of canonical proliferative and survival Akt-mTOR signaling, and increased pro-apoptotic caspase activation. Interestingly, FAK inhibition alone induced feedback activation of pro-survival Erk signaling, which was abrogated by co-treatment with Hsp90 inhibitors. Both Hsp90 and FAK inhibitors are undergoing clinical evaluation. Our studies suggest the tandem of Hsp90 and FAK inhibitors may provide an effective treatment option for NSCLC patients.
发现有效的药物组合是提高患者生存率的一种有前景的策略。本研究探讨热休克蛋白90（Hsp90）抑制与粘着斑激酶（FAK）抑制剂联合使用对非小细胞肺癌细胞（NSCLC细胞）生长的影响。我们的数据表明，17-N-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG），一种经过充分研究的Hsp90抑制剂，与FAK抑制剂PF-573228协同作用，对NSCLC细胞的生长具有抑制作用。使用另一种化学结构不同的Hsp90抑制剂STA-9090证实了这种联合效应，该抑制剂目前正在进行3期临床评估。与单药处理相比，用Hsp90和FAK抑制剂共同处理NSCLC细胞显著增强了对长期集落形成的抑制作用。抑制FAK加剧了17-AAG诱导的G2期细胞周期阻滞和膜联蛋白V凋亡染色。进一步的机制研究表明，Hsp90和FAK抑制剂联合使用降低了经典增殖和存活Akt-mTOR信号的活性，并增加了促凋亡半胱天冬酶的激活。有趣的是，单独抑制FAK会诱导促存活Erk信号的反馈激活，而与Hsp90抑制剂共同处理可消除这种激活。Hsp90和FAK抑制剂都正在进行临床评估。我们的研究表明，Hsp90和FAK抑制剂联合使用可能为NSCLC患者提供一种有效的治疗选择。
