Sinha Abhilasha, Zou Yong, Patel Ayushi S, Yoo Seungyeul, Jiang Feng, Sato Takashi, Kong Ranran, Watanabe Hideo, Zhu Jun, Massion Pierre P, Borczuk Alain C, Powell Charles A
Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Cancers (Basel). 2022 Jan 29;14(3):708. doi: 10.3390/cancers14030708.
Lung cancer is the most common cause of cancer-related deaths in both men and women, accounting for one-quarter of total cancer-related mortality globally. Lung adenocarcinoma is the major subtype of non-small cell lung cancer (NSCLC) and accounts for around 40% of lung cancer cases. Lung adenocarcinoma is a highly heterogeneous disease and patients often display variable histopathological morphology, genetic alterations, and genomic aberrations. Recent advances in transcriptomic and genetic profiling of lung adenocarcinoma by investigators, including our group, has provided better stratification of this heterogeneous disease, which can facilitate devising better treatment strategies suitable for targeted patient cohorts. In a recent study we have shown gene expression profiling identified novel clustering of early stage LUAD patients and correlated with tumor invasiveness and patient survival. In this study, we focused on copy number alterations in LUAD patients. SNP array data identified amplification at chromosome 12q15 on MDM2 locus and protein overexpression in a subclass of LUAD patients with an invasive subtype of the disease. High copy number amplification and protein expression in this subclass correlated with poor overall survival. We hypothesized that MDM2 copy number and overexpression predict response to MDM2-targeted therapy. In vitro functional data on a panel of LUAD cells showed that MDM2-targeted therapy effectively suppresses cell proliferation, migration, and invasion in cells with MDM2 amplification/overexpression but not in cells without MDM2 amplification, independent of p53 status. To determine the key signaling mechanisms, we used RNA sequencing (RNA seq) to examine the response to therapy in MDM2-amplified/overexpressing p53 mutant and wild-type LUAD cells. RNA seq data shows that in MDM2-amplified/overexpression with p53 wild-type condition, the E2F → PEG10 → MMPs pathway is operative, while in p53 mutant genetic background, MDM2-targeted therapy abrogates tumor progression in LUAD cells by suppressing epithelial to mesenchymal transition (EMT) signaling. Our study provides a potentially clinically relevant strategy of selecting LUAD patients for MDM2-targeted therapy that may provide for increased response rates and, thus, better survival.
肺癌是男性和女性癌症相关死亡的最常见原因，占全球癌症相关总死亡率的四分之一。肺腺癌是非小细胞肺癌（NSCLC）的主要亚型，约占肺癌病例的40%。肺腺癌是一种高度异质性疾病，患者通常表现出不同的组织病理学形态、基因改变和基因组畸变。包括我们团队在内的研究人员在肺腺癌转录组学和基因谱分析方面的最新进展，为这种异质性疾病提供了更好的分层，这有助于制定适合特定患者群体的更好治疗策略。在最近的一项研究中，我们表明基因表达谱分析确定了早期肺腺癌患者的新聚类，并与肿瘤侵袭性和患者生存率相关。在本研究中，我们重点关注肺腺癌患者的拷贝数改变。SNP阵列数据确定了MDM2基因座在12q15染色体上的扩增以及疾病侵袭性亚型的一部分肺腺癌患者中的蛋白过表达。该亚类中的高拷贝数扩增和蛋白表达与总体生存率差相关。我们假设MDM2拷贝数和过表达可预测对MDM2靶向治疗的反应。一组肺腺癌细胞的体外功能数据表明，MDM2靶向治疗可有效抑制MDM2扩增/过表达细胞的细胞增殖、迁移和侵袭，但对无MDM2扩增的细胞无效，且与p53状态无关。为了确定关键信号机制，我们使用RNA测序（RNA seq）来检查MDM2扩增/过表达的p53突变型和野生型肺腺癌细胞对治疗的反应。RNA seq数据表明，在p53野生型条件下的MDM2扩增/过表达中，E2F→PEG10→MMPs途径起作用，而在p53突变基因背景下,MDM2靶向治疗通过抑制上皮-间质转化（EMT）信号传导消除肺腺癌细胞中的肿瘤进展。我们的研究提供了一种潜在的临床相关策略，用于选择肺腺癌患者进行MDM2靶向治疗，这可能会提高反应率，从而改善生存率。
