Oncotarget

Research Papers:

Radioresistant human lung adenocarcinoma cells that survived multiple fractions of ionizing radiation are sensitive to HSP90 inhibition

Roberto Gomez-Casal, Michael W. Epperly, Hong Wang, David A. Proia, Joel S. Greenberger and Vera Levina _

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Oncotarget. 2015; 6:44306-44322. https://doi.org/10.18632/oncotarget.6248

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Abstract

Roberto Gomez-Casal1,2, Michael W. Epperly1,3, Hong Wang1,4, David A. Proia5, Joel S. Greenberger1,3, Vera Levina1,2,6

1University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

2Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

3Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA

4Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA

5Synta Pharmaceuticals Corp., Lexington, MA, USA

6Current address: Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

Correspondence to:

Vera Levina, e-mail: levinav@upmc.edu

Keywords: lung adenocarcinoma, fractionated ionizing radiation, radioresistance mechanisms, DNA repair, heat shock protein-90

Received: August 14, 2015     Accepted: October 14, 2015     Published: October 27, 2015

ABSTRACT

Despite the common usage of radiotherapy for the treatment of NSCLC, outcomes for these cancers when treated with ionizing radiation (IR) are still unsatisfactory. A better understanding of the mechanisms underlying resistance to IR is needed to design approaches to eliminate the radioresistant cells and prevent tumor recurrence and metastases. Using multiple fractions of IR we generated radioresistant cells from T2821 and T2851 human lung adenocarcinoma cells. The radioresistant phenotypes present in T2821/R and T2851/R cells include multiple changes in DNA repair genes and proteins expression, upregulation of EMT markers, alterations of cell cycle distribution, upregulation of PI3K/AKT signaling and elevated production of growth factors, cytokines, important for lung cancer progression, such as IL-6, PDGFB and SDF-1 (CXCL12). In addition to being radioresistant these cells were also found to be resistant to cisplatin.

HSP90 is a molecular chaperone involved in stabilization and function of multiple client proteins implicated in NSCLC cell survival and radioresistance. We examined the effect of ganetespib, a novel HSP90 inhibitor, on T2821/R and T2851/R cell survival, migration and radioresistance. Our data indicates that ganetespib has cytotoxic activity against parental T2821 and T2851 cells and radioresistant T2821/R and T2851/R lung tumor cells. Ganetespib does not affect proliferation of normal human lung fibroblasts. Combining IR with ganetespib completely abrogates clonogenic survival of radioresistant cells.

Our data show that HSP90 inhibition can potentiate the effect of radiotherapy and eliminate radioresistant and cisplatin -resistant residual cells, thus it may aid in reducing NSCLC tumor recurrence after fractionated radiotherapy.


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