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.
Highlights
IntroductionSystemic therapies fail to cure most lung cancers [2,3,4,5]
Lung cancer is responsible for one-third of all cancer deaths
All three AC cell lines were sensitive to the antiproliferative effects of ganetespib, with the T2821 cell line showing the greatest sensitivity (IC50, 21.2 ±0.9 nM), and with lower sensitivities detected in T2851 (IC50, 43.4 ±1.5 nM) and A549 (IC50, 49.9 ±1.9 nM) cell lines (Figure 1A)
Summary
Systemic therapies fail to cure most lung cancers [2,3,4,5]. IR therapy is an integral component of the treatment for NSCLC [3,6,7]. Intrinsic or acquired resistance is considered to be the main limiting factor for the efficacy of IR in long-term treatment of lung cancer [7,8]. AC sensitivity to IR depends on the oncogenic genotype which is present. Tumors bearing epidermal growth factor receptor (EGFR) mutations, or those expressing the echinoderm microtubule-associated protein-like 4 gene fused to the anaplastic lymphoma kinase (EML4-ALK) gene, are largely radiosensitive. IR therapy is routinely ordered for patients without determination of the dominant oncogenic mutations that are present [12]
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