Cancer genomics of lung cancer including malignant mesothelioma: A brief overview of current status and future prospects

Our plain-English summary of Cancer genomics of lung cancer including malignant mesothelioma: A brief overview of current status and future prospects, by S.C. Jhanwar, X.L. Xu, A.H. Elahi, et al (Advances in Biological Regulation, 2020).

The study

• Authors: S.C. Jhanwar, X.L. Xu, A.H. Elahi, D.H. Abramson
• Journal: Advances in Biological Regulation
• Published: 2020;78:100723
• Type of article: Review
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Cancer as a genetic disease is by now well recognized. Genomic analysis of cancer cells, therefore, has greatly enhanced our ability to identify genetic alterations associated with various cancer types, including both lympho-hematopoietic as well as solid tumors. Chronic myeloid leukemia (CML), based on the specific diagnostic genetic abnormality has served as a prototype disease to clearly demonstrate the significance of the genomic analysis of cancer in identifying targeted therapy. Such a success has provided extra ordinary opportunities to investigate the role of genetic abnormalities and the pathways amenable to targeted therapy, not only in blood cancers but solid tumors such as Lung, Brain, Colon, Renal, Breast cancers as well as other epithelial and mesenchymal tumors. The main focus of this presentation is to illustrate the role of genomic analysis in targeting lung cancer, based on abnormalities or the pathways deregulated in tumor cells from individual patients. Lung cancer is one of the most common epithelial cancers associated with chronic inflammation due to cigarette smoking and other environmental carcinogens, and includes four distinct histologic type; non-small cell lung cancer (NSCLC); small cell lung cancer (SCLC) and squamous cell lung cancer. According to current estimates, 1.3 million cases of lung cancer are expected to be diagnosed worldwide annually, resulting in one million deaths. Since the discovery that patient's tumors with specific mutations in the EGFR may be sensitive to targeted therapeutic approach and the subsequent realization that the such mutations in the gene are not as prevalent, several cancer centers including ours initiated intense efforts to find other mutations or genomic alterations, which may serve as targets of specific therapy. Such efforts have successfully resulted in a battery of genes such as KRAS, ALK, C-MET, HER-2/neu, ROS1, etc., which have helped oncologists to triage the patients for personalized therapies. A significant proportion of patients with lung cancer, however, do not show any of the above genetic abnormalities. Approximately 90% of lung cancers exhibit RB1 mutation/deletion and or KRAS mutations, therefore, the signaling pathways, which regulate multistep tumorigenesis in lung cancer, are important for the treatment of histologic subtypes of lung cancer, which includes NSCLC & SCLC. Equally important was the findings that similar signaling pathways are also shared by other solid tumor types. We have investigated the role of these pathways to target these cancers and develop new strategies to treat lung, brain and related cancers. In addition, our translational studies in other tumor types such as NF2 related malignancies, specifically, Malignant Mesothelioma (MM), in which NF2 related pathway amenable to targeted therapies was identified. Selected examples representing experimental approaches will be discussed to illustrate the critical role of translational research in developing novel therapeutics for the successful and durable responses in some of these cancer types.

Copyright © 2020 Elsevier Ltd. All rights reserved.

In plain English

This article is a brief overview of genetic changes in lung cancer and malignant mesothelioma, and of how those changes might guide targeted drug treatment. Much of it summarizes earlier published work, including the authors' own. It also describes laboratory experiments on cancer cell lines, not on patients. The authors assembled 10 KRAS-activated, 2 retinoblastoma and 25 KRAS wild type cell lines. They reported that cell lines from BRAF, EGFR and KRAS-activated tumors, including non-small cell lung cancer, were sensitive to an experimental compound called HX531. The tested RB1-mutated retinoblastoma cells, osteosarcoma cells and normal fibroblast cells were not sensitive. HX531 was described as breaking up a protein complex, which led to cell cycle arrest and cell death. Combined with MEK inhibitors, it had a synergistic effect. For mesothelioma, the article reviewed earlier findings and stated that about 90% of cases show inactivation of the NF2 gene. The article did not study asbestos exposure. The authors concluded that targeting RxRG may be a good strategy to treat KRAS-activated cancers.

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: Narrative overview (review) of cancer genomics in lung cancer and malignant mesothelioma, including a summary of the authors' earlier work and new laboratory (in vitro) cell-line experiments
• Who was studied: No patients were studied. The laboratory experiments used cancer cell lines: 10 KRAS-activated, 2 retinoblastoma and 25 KRAS wild type cell lines, some developed in the authors' laboratory
• Exposure: No asbestos exposure was studied. The experiments tested the RxRG antagonist HX531, other RxRG antagonists, the RxRG agonist bexarotene, and MEK inhibitors on cell lines
• Main results:
  • Cell lines from BRAF, EGFR and KRAS-activated tumors, including non-small cell lung cancer, were sensitive to HX531. RB1-mutated retinoblastoma, osteosarcoma and normal fibroblast cells were not sensitive.
  • In lung cancer cells, a protein complex the authors call the S-phase complex came apart after HX531 treatment, resulting in cell cycle arrest and cell death
  • In combination experiments, a MEK inhibitor alone caused moderate growth inhibition, and the combination with HX531 had a synergistic effect. No statistics were given in the text.
  • In its review of mesothelioma, the article stated that about 90% of malignant mesotheliomas show functional inactivation of the NF2 gene. This is a statement drawn from the literature and the authors' earlier work, not a new measurement.
  • The article summarized the authors' earlier published study reporting that restoring the merlin protein in NF2-deficient mesothelioma cell lines negatively regulated focal adhesion kinase (FAK)
• The authors' conclusion: The authors concluded that RxRG is an important synthetic lethal gene in KRAS-activated cancers and that targeting this pathway may be a good strategy to treat such cancers

Topics

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

Medical terms in this study, explained in our Lexicon: Lung Cancer, Mesothelioma, Targeted Therapy, Mesenchymal Tumor, Chronic Inflammation, Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Squamous Cell Carcinoma.

Related studies

• Clinical Trials with Oncolytic Measles Virus: Current Status and Future Prospects — P. Msaouel, M. Opyrchal, et al. (2018)
• Malignant mesothelioma. Current status and future prospects — J. Aisner, P.H. Wiernik (1978)
• Immunotherapy for malignant pleural mesothelioma. Current status and future prospects — R.M. Wong, I. Ianculescu, et al. (2014)
• Genomic Landscape of Malignant Mesotheliomas — S. Kato, B.N. Tomson, et al. (2016)
• Syntenic relationships between genomic profiles of fiber-induced murine and human malignant mesothelioma — D. Jean, E. Thomas, et al. (2011)
• Translating mesothelioma molecular genomics and dependencies into precision oncology-based therapies — T.K. Hinz, L.E. Heasley (2020)

Browse return to medical research.