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.
Highlights
Lung cancer is the leading cause of cancer death in the United States, with non-small cell lung cancer (NSCLC) constituting more than half of all lung cancer cases [1].Adenocarcinoma (AC) is the major histological subtype of non-small cell lung cancer
We recently reported that ionizing radiation (IR) treatment upregulated the level of pAKT in T2821 and T2851 lung adenocarcinoma cells, which could be blocked by the HSP90 inhibitor ganetespib [28]
Chronic exposure to IR induced an adaptive response in the tumor cells resulting in tolerance to subsequent IR treatments with the generation of radioresistant residual cells that increase the risk of tumor recurrence, metastasis and negatively affects survival outcomes [31, 49, 50]
Summary
Lung cancer is the leading cause of cancer death in the United States, with non-small cell lung cancer (NSCLC) constituting more than half of all lung cancer cases [1]. Adenocarcinoma (AC) is the major histological subtype of non-small cell lung cancer. Radiotherapy (RT), either alone or in combination with surgery or chemotherapy is among the primary treatment protocols for NSCLC [2,3,4]. The therapeutic outcomes in many www.impactjournals.com/oncotarget cases are not satisfactory. Tumor radioresistance leads to a reduction in the efficiency of RT with corresponding tumor recurrence and metastasis [2,3,4]. It is important to investigate the cellular mechanisms leading to this loss of radiosensitivity and to discover potential therapeutic compounds which might significantly improve the efficacy of these treatments and prevent metastasis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
