Abstract 2491: Effect of HSP90 inhibitor ganetespib on stemness in small cell lung cancer

Abstract

Abstract Small cell lung cancer (SCLC) is the most aggressive and metastatic form of lung cancer with a 5 year survival rate of less than 7%. Typically, patients are diagnosed with SCLC when the tumor has already widely metastasized. Combination chemotherapy, generally platinum-based plus etoposide is the mainstay first-line treatments for metastatic SCLC. Despite being highly sensitive to first-line therapy treatments, most patients with SCLC experience relapse with resistant disease within 2 years and die from systemic metastasis. Since there are no approved therapies for the treatment of SCLC, discoveries of therapies that can counteract the spread and relapse of SCLC are needed. Therapy resistance in SCLC can occur through a variety of mechanisms, one possible mechanism might be through the activities of cancer stem-like cells (CSCs) within the SCLC cell population. Different markers, such as ALDH+, CD133+, and uPAR+, are considered as markers of CSCs in SCLC. We used flow cytometry and the Aldefluor kit to separate cells with high and low ALDH activity; flow cytometry and fluorescently- labeled antibody against CD133 and uPAR to separate CD133+ and uPAR + cells. We confirmed that ALDH+/CD133+ and ALDH+/uPAR+ cells were capable of generating tumor spheres in the second and third generations. When we compared SCLC cell lines that were generated from untreated tumors (DMS-53 cell line) with those generated from tumors that were heavily treated (H69 and DMS-114 SCLC cell lines), we found that the percentage of CSCs in DMS-53 cell was significantly lower than that found in H69 and DMS-114 SCLC cell lines. CSCs in SCLC express a distinctive pattern of receptors, signaling molecules, and transcription factors such as ALDHA1, CD133, uPAR, OCT-4, SOX2, STAT3, PKM2, DNA-PK, HIF-1a, and HIF-2a; the upregulation of these factors was determined through analysis of genes and protein expression levels. These proteins are associated with cancer stemness, resistance to conventional therapies, proliferation, and metastasis. Many of these proteins are known to interact with the molecular chaperone heat shock protein 90 (HSP90) and therefore can be targeted simultaneously with HSP90 inhibitors. We used a new HSP90 inhibitor ganetespib, which is showing considerable promise in late stage clinical trials for treatment of other cancer types. Ganetespib used as monotherapy induced cell cycle arrest and apoptosis and effectively inhibited growth of bulk SCLC cells and CSCs growing as tumor spheres. Ganetespib at low nanomolar concentrations significantly potentiates the effect of cisplatin and etoposide in vitro. Further in vivo studies are needed to unravel role played by HSP90 in therapy resistance and metastasis in SCLC. Citation Format: Roberto Gomez-Casal, Peng Zhang, Hong Wang, Paul Gardner, James Herman, Vera Levina. Effect of HSP90 inhibitor ganetespib on stemness in small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2491.