PO.TB03.02 · 肿瘤生物学
鉴定激活部分EMT的蛋白激酶信号网络作为非小细胞肺癌的治疗靶点
Identification of protein kinase signaling networks activating partial EMT as therapeutic targets in non-small cell lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
非小细胞肺癌（NSCLC），其中三分之一为肺鳞状细胞癌（LUSC），是美国癌症相关死亡的主要原因。LUSC治疗主要涉及铂类化疗和免疫检查点阻断。然而，仅有20%的患者获得长期获益，凸显了改善治疗疗效策略的迫切需求。我们已鉴定出部分上皮-间质转化（pEMT）是阻碍LSCC治疗疗效的关键机制。pEMT是一种癌细胞同时表现出上皮和间质特征的细胞状态，与细胞迁移/侵袭增强、存活和治疗耐药相关。因此，我们试图鉴定能够逆转pEMT从而使LSCC对治疗敏感的磷酸化网络。我们已鉴定出一个STE20家族激酶网络是维持LSCC细胞pEMT的核心信号节点。对STE20受抑制的LSCC细胞的RNAseq分析揭示了LSCC的转录重编程，提示其向上皮样表型逆转。与之一致，我们观察到上皮标志物（E-cadherin、EpCAM）表达增加，间质标志物（vimentin、CD44）水平降低。此外，STE20耗竭或抑制抑制了关键的pEMT功能，包括迁移、侵袭和克隆形成潜能。我们目前的研究旨在鉴定所观察到表型的潜在机制。我们的初步分析表明STE20是激活YAP/TAZ和MYC转录程序所必需的。最后，为组合治疗奠定基础，我们使用一个临床相关化合物文库与STE20抑制剂联合进行了高通量筛选。该筛选显示与铂类化疗存在潜在协同作用，我们正在体外和体内对此进行研究。总之，我们发现了一个维持NSCLC细胞pEMT的STE20磷酸化模块，它代表了一个可靶向的可操作性弱点，可用于使NSCLC对一线治疗敏感。
查看英文原文 English abstract
Non-small cell lung cancer (NSCLC), of which one-third are lung squamous cell carcinomas (LUSC), is the leading cause of cancer-related death in the US. LUSC treatments primarily involve platinum-based chemotherapy and immune checkpoint blockade. However, only 20% of patients benefit long-term, underscoring a critical need for strategies that improve treatment efficacy. We have identified partial epithelial-to-mesenchymal transition (pEMT) as a key mechanism hindering treatment efficacy in LSCC. pEMT is a cell state in which cancer cells display epithelial and mesenchymal characteristics, and is associated with heightened cell migration/invasion, survival, and treatment resistance. Therefore, we sought to identify phosphorylation networks that could reverse pEMT and, thereby, sensitize LSCC to treatment. We have identified a STE20-family kinase network as a central signaling node sustaining pEMT in LSCC cells. RNAseq analysis of STE20-inhibited LSCC cells revealed transcriptional reprogramming of LSCC indicative of reversion to an epithelial-like phenotype. Consistently, we observed increased expression of epithelial markers (E-cadherin, EpCAM), and reduced levels of mesenchymal markers (vimentin, CD44). Furthermore, STE20 depletion or inhibition suppressed key pEMT functions, including migration, invasion, and clonogenic potential. Our current studies are aimed at identifying the underlying mechanisms of the observed phenotypes. Our initial analysis indicates that STE20 is required for the activation of the YAP/TAZ and MYC transcriptional programs. Last, to lay the groundwork for combination treatments, we conducted a high-throughput screen using a library of clinically relevant compounds in combination with STE20 inhibitors. This screen showed potential synergism with platinum-based chemotherapy, which we are investigating in vitro and in vivo . In conclusion, we have uncovered a STE20 phosphorylation module that sustains pEMT in NSCLC cells and represents an actionable vulnerability that can be targeted to sensitize NSCLCs to first-line treatments.
利益披露 Disclosure
M. Hamidi, None..
K. Omolo, None..
A. Yarmahmoodi, None..
K. W. Hart, None..
A. Dizon, None..
S. Sitaram, None.