title: Radioresistant human lung adenocarcinoma cells that survived multiple fractions of ionizing radiation are sensitive to HSP90 inhibition.
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.
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.|Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gomez-Casal
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.|Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Epperly
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.|Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Synta Pharmaceuticals Corp., Lexington, MA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Proia
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.|Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Greenberger
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.|Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Current address: Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Vera
authors.initials: V
authors.lastname: Levina
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D010641:Phenotype; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D011838:Radiation-Sensitizing Agents; C533237:STA 9090; D014230:Triazoles; D002945:Cisplatin
keywords: DNA repair; fractionated ionizing radiation; heat shock protein-90; lung adenocarcinoma; radioresistance mechanisms