title: The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells.
abstract: The molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibitor, was evaluated in human lung adenocarcinoma (AC) cells for its ability to potentiate the effects of IR treatment in both in vitro and in vivo. The cytotoxic effects of ganetespib included; G2/M cell cycle arrest, inhibition of DNA repair, apoptosis induction, and promotion of senescence. All of these antitumor effects were both concentration- and time-dependent. Both pretreatment and post-radiation treatment with ganetespib at low nanomolar concentrations induced radiosensitization in lung AC cells in vitro. Ganetespib may impart radiosensitization through multiple mechanisms: such as down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and promotion of cellular senescence. In vivo, ganetespib reduced growth of T2821 tumor xenografts in mice and sensitized tumors to IR. Tumor irradiation led to dramatic upregulation of β-catenin expression in tumor tissues, an effect that was mitigated in T2821 xenografts when ganetespib was combined with IR treatments. These data highlight the promise of combining ganetespib with IR therapies in the treatment of AC lung tumors.
authors.affiliation: The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. gomezcasalr@upmc.edu.|Department of Medicine, The University of Pittsburgh, Pittsburgh, PA 15213, USA. gomezcasalr@upmc.edu.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gomez-Casal
authors.affiliation: The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. bhattacharyac@upmc.edu.|Department of Medicine, The University of Pittsburgh, Pittsburgh, PA 15213, USA. bhattacharyac@upmc.edu.
authors.forename: Chitralekha
authors.initials: C
authors.lastname: Bhattacharya
authors.affiliation: The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. EPPERLY@pitt.edu.|Department of Radiation Oncology, The University of Pittsburgh, Pittsburgh, PA 15213, USA. EPPERLY@pitt.edu.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Epperly
authors.affiliation: The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. basse@imap.pitt.edu.|Department of Immunology, The University of Pittsburgh, Pittsburgh, PA 15213, USA. basse@imap.pitt.edu.
authors.forename: Per H
authors.initials: PH
authors.lastname: Basse
authors.affiliation: The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. how8@pitt.edu.|Department of Biostatistics, The University of Pittsburgh, Pittsburgh, PA 15213, USA. how8@pitt.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Harvard Medical School, Harvard University, 25 Shattuck Street, Boston, MA 02115, USA. xwang30@mgh.harvard.edu.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Wang
authors.affiliation: Synta Pharmaceuticals Corp., 45 Hartwell Avenue, Lexington, MA 02421, USA. roia@syntapharma.com.
authors.forename: David A
authors.initials: DA
authors.lastname: Proia
authors.affiliation: The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. greenbergerjs@UPMC.EDU.|Department of Radiation Oncology, The University of Pittsburgh, Pittsburgh, PA 15213, USA. greenbergerjs@UPMC.EDU.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Greenberger
authors.affiliation: The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. socinskima@upmc.edu.|Department of Medicine, The University of Pittsburgh, Pittsburgh, PA 15213, USA. socinskima@upmc.edu.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Socinski
authors.affiliation: The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA. levinav@upmc.edu.|Department of Medicine, The University of Pittsburgh, Pittsburgh, PA 15213, USA. levinav@upmc.edu.
authors.forename: Vera
authors.initials: V
authors.lastname: Levina
keywords: DNA repair; HSP90 inhibitor ganetespib; apoptosis; cell cycle; ionizing radiation; lung adenocarcinoma; senescence; xenografted tumors