Department of Pharmaceutical Sciences and Markey Cancer Center, College of Pharmacy, University of Kentucky, Lexington, Kentucky, United States of America.
PLoS One. 2021 Aug 26;16(8):e0256416. doi: 10.1371/journal.pone.0256416. eCollection 2021.
The identification of novel therapies, new strategies for combination of therapies, and repurposing of drugs approved for other indications are all important for continued progress in the fight against lung cancers. Antibodies that target immune checkpoints can unmask an immunologically hot tumor from the immune system of a patient. However, despite accounts of significant tumor regression resulting from these medications, most patients do not respond. In this study, we sought to use protein expression and RNA sequencing data from The Cancer Genome Atlas and two smaller studies deposited onto the Gene Expression Omnibus (GEO) to advance our hypothesis that inhibition of SHP-2, a tyrosine phosphatase, will improve the activity of immune checkpoint inhibitors (ICI) that target PD-1 or PD-L1 in lung cancers. We first collected protein expression data from The Cancer Proteome Atlas (TCPA) to study the association of SHP-2 and PD-L1 expression in lung adenocarcinomas. RNA sequencing data was collected from the same subjects through the NCI Genetic Data Commons and evaluated for expression of the PTPN11 (SHP-2) and CD274 (PD-L1) genes. We then analyzed RNA sequencing data from a series of melanoma patients who were either treatment naïve or resistant to ICI therapy. PTPN11 and CD274 expression was compared between groups. Finally, we analyzed gene expression and drug response data collected from 21 non-small cell lung cancer (NSCLC) patients for PTPN11 and CD274 expression. From the three studies, we hypothesize that the activity of SHP-2, rather than the expression, likely controls the expression of PD-L1 as only a weak relationship between PTPN11 and CD274 expression in either lung adenocarcinomas or melanomas was observed. Lastly, the expression of CD274, not PTPN11, correlates with response to ICI in NSCLC.
寻找新的疗法、为联合疗法制定新策略以及重新利用已批准用于其他适应症的药物，这些对于在对抗肺癌方面取得持续进展都非常重要。靶向免疫检查点的抗体可以使患者免疫系统中的免疫热肿瘤显现出来。然而，尽管这些药物导致肿瘤显著消退的报道屡见不鲜，但大多数患者并没有响应。在这项研究中，我们试图利用癌症基因组图谱（TCGA）和两个较小的研究中在基因表达综合数据库（GEO）中存储的蛋白质表达和 RNA 测序数据，推进我们的假说，即抑制酪氨酸磷酸酶 SHP-2 将提高针对 PD-1 或 PD-L1 的免疫检查点抑制剂（ICI）在肺癌中的活性。我们首先从癌症蛋白质组图谱（TCPA）收集蛋白质表达数据，以研究 SHP-2 和 PD-L1 在肺腺癌中的表达关联。通过 NCI 遗传数据共享收集了来自相同对象的 RNA 测序数据，并评估了 PTPN11（SHP-2）和 CD274（PD-L1）基因的表达。然后，我们分析了一系列黑色素瘤患者的 RNA 测序数据，这些患者要么对 ICI 治疗有反应，要么有反应。比较了两组之间的 PTPN11 和 CD274 表达。最后，我们分析了从 21 名非小细胞肺癌（NSCLC）患者收集的基因表达和药物反应数据，用于 PTPN11 和 CD274 的表达。从这三项研究中，我们假设 SHP-2 的活性而不是表达可能控制 PD-L1 的表达，因为在肺腺癌或黑色素瘤中观察到 PTPN11 和 CD274 表达之间仅存在微弱关系。最后，CD274 的表达而不是 PTPN11 的表达与 NSCLC 对 ICI 的反应相关。
