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

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 chemosensitivityvia 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.Lung cancer is one of the most prevalent malignancies and the leading cause of cancer-related deaths worldwide.1 It is histologically classified in two types: non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). While targeted molecular therapies have led to improved treatment outcomes for NSCLC, no progress has been made on therapeutic strategies for SCLC over the past two decades.2 SCLC accounts for nearly 15% of lung cancer cases and exhibits aggressive clinical behavior characterized by rapid growth and metastatic spread to multiple organs such as the brain, liver, and bones.3 Accordingly, about 70% of patients with SCLC present with extensive disease (ED) and distant metastases. Cisplatin-based chemotherapy is standard for patients with ED-SCLC, 4 but despite an initial response, most patients develop chemoresistant disease within 6 months and often become refractory to salvage chemotherapy. 4,5Thus, the median range for ED-SCLC survival is 8-13 months. 6 To improve the poor prognosis of SCLC, it is essential to develop novel effective therapies capable of limiting the progression of multiple-organ metastasis in chemorefractory SCLC. HSP90 is a 90-kDa molecular chaperone whose association is required for the stability and function of numerous "client proteins." 7 Because many of its client proteins-including EGFR (epithelial growth factor receptor), HER2 (human epithelial growth factor receptor 2), AKT and c-Raf (also known as RAF1)-are important participants in the pathways that drive tumor cell survival, proliferation and progression, HSP9...

Impact of MET inhibition on small‐cell lung cancer cells showing aberrant activation of the hepatocyte growth factor/MET pathway

“…We next examined the efficacy of the MET inhibitors crizotinib and golvatinib on tumor progression using our previously established in vivo imaging model with SBC‐5 EGFP‐Eluc‐transfected (SBC‐5/EGFP‐Eluc) cells . Bioluminescent signals were detected in the SBC‐5/EGFP‐Eluc cells, and observed to increase in a time‐dependent manner, consistent with the time‐course of metastasis formation .…”

“…After inoculation, the development of tumors was tracked in live mice by repeated non‐invasive optical imaging of tumor‐specific luciferase activity using the IVIS Lumina XR Imaging System (PerkinElmer, Alameda, CA, USA) as described . The intensity of the bioluminescence signal was analyzed using Living Image 4.0 software (PerkinElmer) by serially quantifying the peak photon flux in a selected region of interest within a given tumor.…”

“…After inoculation, the development of tumors was tracked in live mice by repeated non-invasive optical imaging of tumor-specific luciferase activity using the IVIS Lumina XR Imaging System (PerkinElmer, Alameda, CA, USA) as described. (20) The intensity of the bioluminescence signal was analyzed using Living Image 4.0 software (PerkinElmer) by serially quantifying the peak photon flux in a selected region of interest within a given tumor. The intensity of the bioluminescence signal was corrected to take into account the total area of the region of interest, and the elapsed time for which bioluminescence signals were read by the charge coupled device camera.…”

“…Although activated MET is reported as a prognostic factor for poor clinical outcome in SCLC, the mechanisms underlying the deleterious effects of aberrant activation of the HGF/MET pathway in SCLC have not been clearly elucidated . We previously established a mouse model of multiple‐organ SCLC metastasis, by utilizing natural killer (NK) cell‐depleted SCID mice, to produce an animal model whose tumor distribution resembles that of advanced SCLC patients . The aim of the present study was to evaluate the effect of inhibiting the HGF/MET pathway on tumor progression in SCLC with multi‐organ metastasis, using this in vivo mouse xenograft model, as well as various cell‐based in vitro assays.…”

Foretinib Overcomes Entrectinib Resistance Associated with the NTRK1 G667C Mutation in NTRK1 Fusion–Positive Tumor Cells in a Brain Metastasis Model

“…In both models, the development of tumors was tracked in live mice by repeated noninvasive optical imaging of tumor-specific luciferase activity using the IVIS Lumina XR Imaging System (PerkinElmer) as described previously (25). The intensity of the bioluminescence signal was analyzed using Living Image 4.0 software (PerkinElmer) by serially quantifying the peak photon flux in a selected region of interest (ROI) within a given tumor.…”