Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, U.S.A.
Anticancer Res. 2021 Jan;41(1):91-99. doi: 10.21873/anticanres.14754.
BACKGROUND/AIM: 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.
背景/目的：小细胞肺癌（SCLC）侵袭性强，预后不良。虽然 SCLC 对化疗的反应优于其他类型的肺癌，但由于其频繁复发，难以治愈。需要确定新的药物和分子靶点。
我们研究了 HIV 蛋白酶抑制剂奈非那韦对 SCLC 细胞的影响，并使用 SCLC 患者来源异种移植（PDX）小鼠模型进行了临床前治疗研究。
奈非那韦在体外抑制 SCLC 细胞增殖并诱导细胞死亡，这是通过诱导未折叠蛋白反应（UPR）、抑制哺乳动物/雷帕霉素靶蛋白（mTOR）激活以及降低 SCLC 相关分子（如achaete-scute 同源物 1 [ASCL1]）的表达来实现的。在体内，奈非那韦抑制 SCLC PDX 肿瘤的生长，这与 UPR 的诱导和 ASCL1 表达的降低相关。
奈非那韦在体外和体内对 SCLC 均具有高度疗效，表明奈非那韦可能被纳入 SCLC 患者的临床试验。
