Organ-specific efficacy of HSP90 inhibitor in multiple-organ metastasis model of chemorefractory small cell lung cancer

Int J Cancer. 2016 Mar 1;138(5):1281-9. doi: 10.1002/ijc.29858. Epub 2015 Oct 13.

Abstract

Small-cell lung cancer (SCLC) accounts for nearly 15% of lung cancer cases and exhibits aggressive clinical behavior characterized by rapid growth and metastatic spread to multiple organs. About 70% of patients with SCLC present with extensive disease and distant metastases at diagnosis. HSP90 is a 90-kDa molecular chaperone whose association is required for the stability and function of its numerous "client proteins." Here, we assessed the therapeutic potential of the HSP90 inhibitor 17-DMAG in SCLC. Notably, 17-DMAG hindered the viability of human SCLC cell lines-regardless of their chemosensitivity-via the decreased expression of client proteins, including the proto-oncogene c-Raf (also known as RAF1). In an in vivo imaging model of SCLC multiple-organ metastasis with the human SCLC cell line SBC-5, treatment with 17-DMAG remarkably inhibited the formation of metastatic sites in the liver, but was ineffective in hindering the progression of bone lesions. The latter was likely the result of activation of osteoclasts. IGF-1, which is supposed to be rich in bone environment, preserved c-Raf expression and maintained viability of SBC-5 cells treated with 17-DMAG. Furthermore, the combined use of a bisphosphonate with 17-DMAG significantly attenuated the progression of metastases in both the liver and the bone. These findings suggest that therapeutic effects of HSP90 inhibitors may be organ-specific and should be carefully monitored in SCLC clinical trials.

Keywords: HSP90 inhibitor; metastasis model; small cell lung cancer.

MeSH terms

  • Animals
  • Benzoquinones / pharmacology
  • Bone Neoplasms / secondary
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Diphosphonates / administration & dosage
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Humans
  • Imidazoles / administration & dosage
  • Lactams, Macrocyclic / pharmacology
  • Liver Neoplasms / secondary
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Organ Specificity
  • Proto-Oncogene Proteins c-raf / analysis
  • Small Cell Lung Carcinoma / drug therapy*
  • Small Cell Lung Carcinoma / pathology
  • Zoledronic Acid

Substances

  • Benzoquinones
  • Diphosphonates
  • HSP90 Heat-Shock Proteins
  • Imidazoles
  • Lactams, Macrocyclic
  • 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
  • Zoledronic Acid
  • Proto-Oncogene Proteins c-raf