Combination of heat shock protein 90 and focal adhesion kinase inhibitors synergistically inhibits the growth of non-small cell lung cancer cells.

Philip J Webber,Suresh S Ramalingam,Min Qui,Chanhee Park,Haian Fu,Fadlo R Khuri,Yuhong Du

doi:10.18632/oncoscience.245

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.

Highlights

Lung cancer is the leading cause of death worldwide and the leading cause of cancer related deaths in the United States accounting for approximately 159,480 deaths in 2013 [1]
In order to explore the therapeutic potential for treatment with the combination of heat shock protein 90 (Hsp90) and focal adhesion kinase (FAK) inhibitors, we carried out the CellTiter-Blue cell viability assay in dose-response format in three different NSCLC cell lines
Hsp90 and FAK proteins hold potential as potent anti-cancer targets, and the expression and activity of each is correlated with cancer [7, 21,22,23,24]

Summary

Introduction

Lung cancer is the leading cause of death worldwide and the leading cause of cancer related deaths in the United States accounting for approximately 159,480 deaths in 2013 [1]. The 5-year survival rate of those diagnosed with lung cancer is approximately 16% despite recent advancements in therapy, necessitating the development of rapidly applicable and effective treatments for clinical use [2]. The development of novel combinations may provide a route for better patient outcome using currently approved therapies or strategies undergoing late phase clinical evaluation. Geldanamycin (GA) is an ansamycin antibiotic that binds and inhibits the ATP dependent function of Hsp preventing the folding of client proteins, and many inhibitors used are based on the GA structure [8,9,10,11,12]. STA-9090 is a novel non-geldanamycin second generation inhibitor currently undergoing phase 2 clinical evaluation, and STA-9090 performed better in a mastocytoma xenograft model when compared to 17-AAG suggesting a more favorable therapeutic profile [20]

Methods

Results

Conclusion