Nelfinavir Inhibits the Growth of Small-cell Lung Cancer Cells and Patient-derived Xenograft Tumors

• Published in: Anticancer research 2021-01, Vol.41 (1), p.91-99
• Main Authors: Kawabata, Shigeru, Connis, Nick, Gills, Joell J, Hann, Christine L, Dennis, Phillip A
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; ASCL1 protein; Biomarkers; Cell death; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Chemotherapy; Clinical trials; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Repositioning; Female; HIV; Homology; Human immunodeficiency virus; Humans; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice; Nelfinavir; Nelfinavir - pharmacology; Nelfinavir - therapeutic use; Patients; Protease inhibitors; Protein folding; Proteinase inhibitors; Rapamycin; Small cell lung carcinoma; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - metabolism; Small Cell Lung Carcinoma - pathology; Target recognition; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tumors; Unfolded Protein Response - drug effects; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.14754

Small-cell lung cancer (SCLC) is aggressive and confers poor prognosis. Although SCLC shows more response to chemotherapy than other types of lung cancer, it is difficult to cure because of its frequent recurrence. New drugs and molecular targets need to be identified. We investigated the effect of nelfinavir, an HIV protease inhibitor, on SCLC cells and in preclinical treatment studies using SCLC patient-derived xenograft (PDX) mouse models. Nelfinavir inhibited SCLC cell proliferation and induced cell death in vitro, which was caused by induction of the unfolded protein response (UPR), inhibition of mammalian/mechanistic target of rapamycin (mTOR) activation, and reduction in the expression of SCLC-related molecules such as achaete-scute homolog 1 (ASCL1). In vivo, nelfinavir inhibited the growth of SCLC PDX tumors, which correlated with the induction of UPR and reduced expression of ASCL1. Nelfinavir is highly effective in SCLC in vitro and in vivo, suggesting possible incorporation of nelfinavir into clinical trials for patients with SCLC.