Gene and MicroRNA Perturbations of Cellular Response to Pemetrexed Implicate Biological Networks and Enable Imputation of Response in Lung Adenocarcinoma

Our plain-English summary of Gene and MicroRNA Perturbations of Cellular Response to Pemetrexed Implicate Biological Networks and Enable Imputation of Response in Lung Adenocarcinoma, by E.R. Gamazon, M.R. Trendowski, Y. Wen, et al (Scientific Reports, 2018).

The study

• Authors: E.R. Gamazon, M.R. Trendowski, Y. Wen, C. Wing, S.M. Delaney, W. Huh, S. Wong, N.J. Cox, M.E. Dolan
• Journal: Scientific Reports
• Published: 2018;8(1):733
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pemetrexed is indicated for non-small cell lung carcinoma and mesothelioma, but often has limited efficacy due to drug resistance. To probe the molecular mechanisms underlying chemotherapeutic response, we performed mRNA and microRNA (miRNA) expression profiling of pemetrexed treated and untreated lymphoblastoid cell lines (LCLs) and applied a hierarchical Bayesian method. We identified genetic variation associated with gene expression in human lung tissue for the most significant differentially expressed genes (Benjamini-Hochberg [BH] adjusted p < 0.05) using the Genotype-Tissue Expression data and found evidence for their clinical relevance using integrated molecular profiling and lung adenocarcinoma survival data from The Cancer Genome Atlas project. We identified 39 miRNAs with significant differential expression (BH adjusted p < 0.05) in LCLs. We developed a gene expression based imputation model of drug sensitivity, quantified its prediction performance, and found a significant correlation of the imputed phenotype generated from expression data with survival time in lung adenocarcinoma patients. Differentially expressed genes (MTHFD2 and SUFU) that are putative targets of differentially expressed miRNAs also showed differential perturbation in A549 fusion lung tumor cells with further replication in A549 cells. Our study suggests pemetrexed may be used in combination with agents that target miRNAs to increase its cytotoxicity.

In plain English

This laboratory study examined how cells respond to pemetrexed, a chemotherapy drug for non-small cell lung carcinoma and mesothelioma. It did not study asbestos exposure, and it analyzed no mesothelioma cells or patients. The authors treated 11 lymphoblastoid cell lines chosen as the most sensitive or resistant to the drug. They measured changes in gene activity (mRNA) and microRNAs. They reported 39 microRNAs that changed significantly. In all 11 lines, the gene MTHFD2 increased while hsa-miR-202, a predicted regulator of it, decreased. MTHFD2 also rose in treated A549 lung adenocarcinoma cells. In public data on 230 lung adenocarcinoma patients, whose drug treatment was not reported, 17 had MTHFD2 alterations. Among patients with survival data, 8 of these 17 had died (median survival 23.36 months), against 55 of 188 without alterations (45.31 months; one-sided logrank test p = 0.06). A model built from the cell lines to predict drug sensitivity was associated with survival time in these patients. The authors concluded that combination therapies with pemetrexed should be further evaluated, and they called for further replication.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory cell-line experiment (gene and microRNA expression profiling before and after drug treatment), with follow-up analyses of public datasets (GTEx lung tissue, TCGA lung adenocarcinoma) and replication in A549 lung cancer cells
• Who was studied: 11 lymphoblastoid cell lines selected from 84 previously tested lines derived from unrelated Utah residents of Northern and Western European ancestry; A549 human lung adenocarcinoma cells; public data on 230 lung adenocarcinoma patients (TCGA) and lung tissue from 278 individuals (GTEx)
• Exposure: The chemotherapy drug pemetrexed (0.5 µM for 24 hours in the lymphoblastoid cell lines; 10 or 100 µM in A549 cells). No asbestos or fiber exposure was studied.
• Main results:
  • In the 11 lymphoblastoid cell lines, 39 microRNAs showed significant differential expression after pemetrexed treatment.
  • In all 11 lymphoblastoid cell lines, pemetrexed increased MTHFD2 expression while hsa-miR-202, a putative regulator of MTHFD2, decreased.
  • Nine of the 20 most significantly altered genes had significant cis-acting eQTLs (genetic variants linked to gene expression) in human lung tissue from GTEx.
  • In A549 lung cancer cells, PMAIP1 expression increased 12-fold at 48 hours after treatment with 10 µM pemetrexed.
  • Among the TCGA lung adenocarcinoma samples, 17 of 230 patients (7%) showed MTHFD2 alterations (amplification, mutation, or mRNA upregulation).
  • In the subgroup of TCGA lung adenocarcinoma patients with survival data, 8 of the 17 with MTHFD2 alterations had died, with a median survival of 23.36 months. Of the 188 without alterations, 55 had died, with a median survival of 45.31 months.
  • The authors reported that MTHFD2 amplification or upregulation was associated with shorter median survival in the TCGA lung adenocarcinoma patients (one-sided logrank test p-value of 0.06).
  • In TCGA lung adenocarcinoma patients, median survival was 32.07 months for cases with UCHL1 and UCHL3 alterations and 45.31 months for cases without them (51 of 176 without alterations deceased). Amplification was associated with shortened median survival (p = 0.041).
  • Applied to TCGA lung adenocarcinoma tumor data, the gene-expression model of drug sensitivity built from the cell lines was associated with survival time. Patients surviving less than 2 months had lower imputed sensitivity to pemetrexed (p = 0.006).
• The authors' conclusion: The authors concluded that combination therapies involving miRNAs or small molecule inhibitors, HDAC inhibitors, or proteasome inhibitors should be further evaluated as ways to enhance the cytotoxicity of pemetrexed.
• Limitations the authors state:
  • The drug regimen of the TCGA lung adenocarcinoma patients is not reported in that dataset.
  • Directly measured drug response data are generally not available for the TCGA samples, so drug response there was imputed.
  • The imputation model findings require additional replication.
  • The link between PMAIP1 and pemetrexed response needs a replication study with a larger sample size.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Lung Adenocarcinoma, Carcinoma, Mesothelioma, Molecular Profiling, A549 Cells.

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