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Author Notes:

Email Address :Yuhong Du :dyuhong@emory.edu

We would like to thank the NCI/DTP for its Oncology drug set. H.F. is Georgia Research Alliance Distinguished Investigator.

The authors have no financial conflict of interest related to the reported studies.

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Research Funding:

National Institutes of Health Grants P01 CA116676 (to F.R.K and H.F.)

Georgia Cancer Coalition of Georgia Research Alliance (to F.R.K., H.F. and S.S.R)

Emory Winship Cancer Institute Kennedy seed grant (to Y.D)

Keywords:

  • Hsp90 inhibitor
  • FAK inhibitor
  • synergistic effect
  • non-small cell lung cancer (NSCLC)
  • Akt-mTOR signaling

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

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Journal Title:

Oncoscience

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Type of Work:

Article | Final Publisher PDF

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.

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© 2015 Webber et al.

This is an Open Access article distributed under the terms of the Creative Commons Attribution 3.0 Unported License ( http://creativecommons.org/licenses/by/3.0/), which permits distribution, public display, and publicly performance, distribution of derivative works, making multiple copies, provided the original work is properly cited. This license requires copyright and license notices be kept intact, credit be given to copyright holder and/or author.

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