Abstract 684: Nelfinavir inhibits the growth of small cell lung cancer cells and patient-derived xenograft tumors

Abstract

Abstract Small cell lung cancer (SCLC) is an aggressive lung cancer with a poor prognosis that is characterized by frequent metastasis at the time of diagnosis. Although SCLC is more responsive to chemotherapy and radiation therapy compared to other types of lung cancer, cure is difficult because of frequent recurrence. Molecular alterations in SCLC include inactivation of TP53 and RB1, high copy number of Myc family, and amplifications of FGFR1 and SOX2. Additionally, achaete-scute homolog 1 (ASCL1), a transcription factor for development of pulmonary neuroendocrine cells, is a lineage-dependent oncogene for SCLC. New drugs and molecular targets need to be identified. Previously, we reported nelfinavir (NFV), a HIV protease inhibitor, inhibited proliferation of non-small cell lung cancer (NSCLC) cells in vitro and human NSCLC xenograft tumors through induction of the unfolded protein response (UPR). Here we demonstrate that the effect of NFV in SCLC cells and preclinical treatment studies using SCLC patient-derived xenograft (PDX) mouse models. NFV inhibited SCLC cell proliferation and induced cell death in vitro. Activating transcription factor 4 (ATF4), a marker of the UPR, was rapidly increased, whereas Myc was decreased after 4 hr treatment with NFV. AMP-activated protein kinase (AMPK), which plays a role in cellular energy homeostasis, was activated in the early phase of NFV treatment, whereas the mammalian target of rapamycin (mTOR) that is a serine/threonine kinase that regulates cell growth, was inactivated. NFV inhibited the expression of SOX2, ASCL1 and Aurora B in a cell line- and time-dependent manner. Taken together, NFV had pleiotropic effects against multiple targets during the inhibition of SCLC cell proliferation. In vivo, NFV inhibited growth of SCLC PDX tumors, which correlated with induction of the UPR and decreased expression of ASCL1 and Aurora B. Collectively, these findings show that NFV is highly effective in SCLC in vitro and in vivo, suggesting possible value of incorporating NFV into clinical trials for patients with SCLC. Citation Format: Shigeru Kawabata, Nick Connis, Chunyu Zhang, Joell J. Gills, Christine L. Hann, Phillip A. Dennis. Nelfinavir inhibits the growth of small cell lung cancer cells and patient-derived xenograft tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 684. doi:10.1158/1538-7445.AM2015-684