Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma

Our plain-English summary of Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma, by H. Yang, D. Xu, Z. Yang, et al (Cancers, 2020).

The study

• Authors: H. Yang, D. Xu, Z. Yang, F. Yao, H. Zhao, R.A. Schmid, R.W. Peng
• Journal: Cancers
• Published: 2020;12(8)
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is driven by the inactivation of tumor suppressor genes (TSGs). An unmet need in the field is the translation of the genomic landscape into effective TSG-specific therapies. Methods: We correlated genomes against transcriptomes of patients' MPM tumors, by weighted gene co-expression network analysis (WGCNA). The identified aberrant biochemical networks and potential drug targets induced by tumor suppressor loss were validated by integrative data analysis and functional interrogation. Results: CDKN2A/2B loss activates G2/M checkpoint and PI3K/AKT, prioritizing a co-targeting strategy for CDKN2A/2B-null MPM. CDKN2A deficiency significantly co-occurs with deletions of anti-viral type I interferon (IFN-I) genes and BAP1 mutations, that enriches the IFN-I signature, stratifying a unique subset, with deficient IFN-I, but proficient BAP1 for oncolytic viral immunotherapies. Aberrant p53 attenuates differentiation and SETD2 loss acquires the dependency on EGFRs, highlighting the potential of differentiation therapy and pan-EGFR inhibitors for these subpopulations, respectively. LATS2 deficiency is linked with dysregulated immunoregulation, suggesting a rationale for immune checkpoint blockade. Finally, multiple lines of evidence support Dasatinib as a promising therapeutic for LATS2-mutant MPM. Conclusions: Systematic identification of abnormal cellular processes and potential drug vulnerabilities specified by TSG alterations provide a framework for precision oncology in MPM.

In plain English

This laboratory and computer-based study did not examine asbestos exposure. The authors analyzed public data on malignant pleural mesothelioma (MPM) tumors from The Cancer Genome Atlas. There were 87 samples with gene-activity data, 81 of them with genetic alteration data and 61 with protein data. The authors looked for groups of genes whose activity changed together when six tumor suppressor genes (CDKN2A/2B, BAP1, NF2, TP53, SETD2 and LATS2) were altered. Loss of CDKN2A/2B was linked with cell-cycle genes, and CDKN2A was often deleted together with anti-viral interferon genes. BAP1 alterations were linked with an interferon gene group. TP53 mutations were linked with lower activity of fat-cell differentiation genes, and SETD2 alterations with EGFR-family genes. LATS2 alterations were linked with immune-regulation genes. In a separate published cohort of cancer patients treated with immune checkpoint drugs, LATS1/2 mutations were associated with better survival. In laboratory tests, MPM cell lines with LATS1/2 alterations were the most sensitive to the drug Dasatinib. The authors concluded that the work provides a framework for biomarker-guided precision treatment and that further studies are needed to verify the drug vulnerabilities.

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: Computational analysis of public tumor genomic, gene-expression and protein data (weighted gene co-expression network analysis), with laboratory drug-sensitivity tests in cell lines
• Who was studied: Malignant pleural mesothelioma tumor samples from The Cancer Genome Atlas: 87 with RNA-sequencing data, 81 of them with genetic alteration data, and 61 with protein array data. Also MPM cell lines, one normal mesothelial cell line, and a primary MPM culture from one 67-year-old male patient.
• Exposure: No asbestos or fiber exposure was studied. The 'exposures' compared were genetic alterations in six tumor suppressor genes: CDKN2A/2B, BAP1, NF2, TP53, SETD2 and LATS2.
• Main results:
  • In TCGA MPM tumors, CDKN2A/2B loss was positively correlated with a 508-gene 'green' module (Pearson's r = 0.55; p-value = 2 × 10^-7) that was enriched for cell-cycle genes.
  • In MPM samples, CDKN2A and interferon-family genes were significantly deleted together.
  • BAP1 alterations in MPM were positively correlated only with the 'red' module, which is enriched for type I interferon pathway genes (r = 0.41; p-value = 2 × 10^-4).
  • TP53 mutations were negatively correlated with a 125-gene 'purple' module (r = -0.37) that was enriched for adipocyte differentiation and lipid metabolism genes.
  • SETD2-altered MPM tumors were positively correlated with a 1143-gene 'turquoise' module that included EGFR-family genes (r = 0.25; p-value = 0.03). E-cadherin protein was significantly increased in SETD2-altered MPM.
  • LATS2 alterations in MPM were positively correlated with the 'brown' module (r = 0.33; p-value = 0.004), which was enriched for immunoregulation genes. PD-L1 was the most significantly increased protein in LATS2-mutant MPM.
  • In a published cohort of cancer patients treated with immune checkpoint blockade (not limited to mesothelioma), mutations of LATS1/2, but not of NF2, were associated with significantly better survival.
  • In cell culture tests, MPM cells with LATS1/2 alterations showed the highest sensitivity to Dasatinib. NF2 mutation status did not appear to predict Dasatinib sensitivity.
• The authors' conclusion: The authors concluded that systematically identifying the gene networks and possible drug vulnerabilities linked with tumor suppressor gene alterations provides a framework for biomarker-guided precision treatment of MPM subsets. They said further studies are needed to verify the drug vulnerabilities and patient-grouping approaches.
• Limitations the authors state:
  • The authors noted that only marginal statistical significance (p-value = 0.04) limits the value of the salmon module linked with TP53 mutations.
  • Protein data for LATS2 and SETD2 were not available in the protein database used.
  • The authors stated that how LATS1/2 modulates the immune response is not yet known and needs further study.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Tumor Suppressor Gene, CDKN2A, BAP1, EGFR.

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