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.