UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
Department of Molecular Biology Interdepartmental Program, University of California, Los Angeles, CA, 90095, USA.
Oncogene. 2023 Feb;42(6):434-448. doi: 10.1038/s41388-022-02558-6. Epub 2022 Dec 13.
Small cell lung cancer (SCLC) remains a lethal disease with a dismal overall survival rate of 6% despite promising responses to upfront combination chemotherapy. The key drivers of such rapid mortality include early metastatic dissemination in the natural course of the disease and the near guaranteed emergence of chemoresistant disease. Here, we found that we could model the regression and relapse seen in clinical SCLC in vitro. We utilized time-course resolved RNA-sequencing to globally profile transcriptome changes as SCLC cells responded to a combination of cisplatin and etoposide-the standard-of-care in SCLC. Comparisons across time points demonstrated a distinct transient transcriptional state resembling embryonic diapause. Differential gene expression analysis revealed that expression of the PEA3 transcription factors ETV4 and ETV5 were transiently upregulated in the surviving fraction of cells which we determined to be necessary for efficient clonogenic expansion following chemotherapy. The FGFR-PEA3 signaling axis guided the identification of a pan-FGFR inhibitor demonstrating in vitro and in vivo efficacy in delaying progression following combination chemotherapy, observed inhibition of phosphorylation of the FGFR adaptor FRS2 and corresponding downstream MAPK and PI3K-Akt signaling pathways. Taken together, these data nominate PEA3 transcription factors as key mediators of relapse progression in SCLC and identify a clinically actionable small molecule candidate for delaying relapse of SCLC.
小细胞肺癌（SCLC）仍然是一种致命疾病，尽管对一线联合化疗有很好的反应，但总体生存率仍为 6%。导致这种快速死亡的主要因素包括疾病自然过程中的早期转移扩散以及几乎可以肯定出现的化疗耐药性疾病。在这里，我们发现可以在体外模拟临床 SCLC 中观察到的消退和复发。我们利用时间分辨 RNA 测序来全面分析 SCLC 细胞对顺铂和依托泊苷联合治疗（SCLC 的标准治疗方法）的反应时转录组变化。对不同时间点的比较显示出一种独特的短暂转录状态，类似于胚胎休眠。差异基因表达分析显示，PEA3 转录因子 ETV4 和 ETV5 的表达在化疗后细胞存活部分中短暂上调，我们确定这对于高效克隆扩增是必需的。FGFR-PEA3 信号轴指导鉴定出一种泛 FGFR 抑制剂，在体外和体内均显示出在联合化疗后延迟进展的疗效，观察到 FGFR 接头 FRS2 和相应的下游 MAPK 和 PI3K-Akt 信号通路的磷酸化被抑制。综上所述，这些数据表明 PEA3 转录因子是 SCLC 复发进展的关键介质，并确定了一种用于延迟 SCLC 复发的临床可操作的小分子候选药物。
