J Hematol Oncol|Charles M Rudin团队揭示AKT和MYC通路在肺癌转分化中的作用

2022年8月5日 0条评论 277次阅读 0人点赞

最新细胞功能及机制文献分享

研究显示，癌症可通过一种称为谱系可塑性的机制增强耐药性，即肿瘤细胞获得一个细胞系的表型特征，该细胞系的存活不再依赖于药物靶点。在肺腺癌（LUAD）中，这种现象包括小细胞和鳞状细胞（LUSC）在获得性抵抗靶向抑制驱动突变背景下的组织学转变。高达9%的EGFR突变患者，因服用奥西美替尼而复发肺癌，其中，LUAD到LUSC的转分化与显著的不良预后相关。2021年10月16日，美国纽约纪念斯隆-凯特琳癌症中心Charles M Rudin团队在Journal of Hematology and Oncology上发表了题为“Comprehensive molecular characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation”的研究论文。在本研究中，团队通过对混合组织学（LUAD/LUSC）肿瘤、转化前/转化后肿瘤和参考非转化LUAD、LUSC样本的显微解剖LUAD和LUSC成分进行了基因组学、表观基因组学、转录组学和蛋白质分析；并通过体外和体内临床前模型的建立进行了相关验证，同时还进行了患者源性异种移植（PDX）治疗，以验证在奥西米替尼治疗后获得LUSC特征的LUAD PDX模型中的潜在治疗靶点。

结果发现，LUSC转分化主要是由转录重编程而不是突变事件驱动的；并且在体内LUAD模型中观察到PI3K/AKT、MYC和PRC2通路基因持续相对上调；在EGFR突变的LUAD模型中激活PI3K/AKT和MYC通路可诱导鳞状细胞特征；将EZH1/2与奥西美替尼联合后，其可在药理学上抑制或预防EGFR突变来源PDX模型中鳞状细胞特征的复发，并抑制EZH1/2或PI3K/AKT信号对奥西美替尼再致敏的耐药鳞状细胞样肿瘤。

至此，团队通过此项研究，提出研究导致组织学转变和最终治疗抵抗的可塑性机制是理解肿瘤演变和设计治疗T-LUSC患者策略的关键。其数据特别指出AKT、MYC和PRC2复合物信号在这种组织学转变中起关键作用。利用EGFR突变体LUAD模型，观察到AKT稳定化和MYC过表达的组合诱导了“鳞状”表型，这一表型通过奥西米替尼治疗进一步加重。对AKT或PRC2复合物活性的药理学抑制显著增强了在EGFR抑制下获得鳞状细胞特征的PDX模型中奥西米替尼治疗的疗效。总体而言，研究团队提供了LUSC转分化的第一个全面的分子特征，并表明了抑制或阻止谱系可塑性的假定驱动因素作为肿瘤治疗潜在靶点的可能性。

《J Hematol Oncol|Charles M Rudin团队揭示AKT和MYC通路在肺癌转分化中的作用》

图 LUSC转化后的表型和途径改变示意图。该项研究提供了LUAD到LUSC转化的渐进信号通路，并确定了几个潜在的靶点，包括PI3K/AKT和MYC通路的激活，以及PRC2的复合作用。

期刊及DOI号

J Hematol Oncol. 2021 Oct 16.

doi: 10.1186/s13045-021-01186-z.

题目

Comprehensive molecular characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation

摘要

背景：Lineage plasticity, the ability to transdifferentiate among distinct phenotypic identities, facilitates therapeutic resistance in cancer. In lung adenocarcinomas (LUADs), this phenomenon includes small cell and squamous cell (LUSC) histologic transformation in the context of acquired resistance to targeted inhibition of driver mutations. LUAD‑to‑LUSC transdifferentiation, occurring in up to 9% of EGFR‑mutant patients relapsed on osimertinib, is associated with notably poor prognosis. We hypothesized that multi‑parameter profiling of the components of mixed histology (LUAD/LUSC) tumors could provide insight into factors licensing lineage plasticity between these histologies.

方法：We performed genomic, epigenomics, transcriptomics and protein analyses of microdissected LUAD and LUSC components from mixed histology tumors, pre‑/post‑transformation tumors and reference non‑transformed LUAD and LUSC samples. We validated our findings through genetic manipulation of preclinical models in vitro and in vivo and performed patient‑derived xenograft (PDX) treatments to validate potential therapeutic targets in a LUAD PDX model acquiring LUSC features after osimertinib treatment.

结果：Our data suggest that LUSC transdifferentiation is primarily driven by transcriptional reprogramming rather than mutational events. We observed consistent relative upregulation of PI3K/AKT, MYC and PRC2 pathway genes. Concurrent activation of PI3K/AKT and MYC induced squamous features in EGFR‑mutant LUAD preclinical models. Pharmacologic inhibition of EZH1/2 in combination with osimertinib prevented relapse with squamous‑features in an EGFR‑mutant patient‑derived xenograft model, and inhibition of EZH1/2 or PI3K/AKT signaling re‑sensitized resistant squamous‑like tumors to osimertinib.

结论：Our findings provide the first comprehensive molecular characterization of LUSC transdifferentiation, suggesting putative drivers and potential therapeutic targets to constrain or prevent lineage plasticity.

关键词：Lineage plasticity, Squamous transdifferentiation, Treatment resistance, Targeted therapy