Combination of heat shock protein 90 and focal adhesion kinase inhibitors synergistically inhibits the growth of non-small cell lung cancer cells
Philip J. Webber1,*, Chanhee Park1,*, Min Qui1,2, Suresh S. Ramalingam3, Fadlo R. Khuri3, Haian Fu1,2,3 and Yuhong Du1,2
1 Department of Pharmacology, Emory University, Atlanta, GA, USA
2 Emory Chemical Biology Discovery Center, Emory University School of Medicine, Emory University, Atlanta, GA, USA
3 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
* These authors contributed equally
Correspondence:
Yuhong Du, email:
Keywords: Hsp90 inhibitor, FAK inhibitor, synergistic effect, non-small cell lung cancer (NSCLC), Akt-mTOR signaling
Received: July 27, 2015 Accepted: September 12, 2015 Published: September 15, 2015
Abstract
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.
