Patients with peritoneal mesothelioma lack epidermal growth factor receptor tyrosine kinase mutations that would make them sensitive to tyrosine kinase inhibitors

Our plain-English summary of Patients with peritoneal mesothelioma lack epidermal growth factor receptor tyrosine kinase mutations that would make them sensitive to tyrosine kinase inhibitors, by N. Kalra, A. Ashai, L. Xi, et al (Oncology Reports, 2012).

The study

• Authors: N. Kalra, A. Ashai, L. Xi, J. Zhang, I. Avital, M. Raffeld, R. Hassan
• Journal: Oncology Reports
• Published: 2012;27(6):1794-800
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The epidermal growth factor receptor (EGFR) is a promising target for cancer therapy. The presence of certain somatic mutations in the tyrosine kinase (TK) domain of the EGFR gene is associated with clinical response to TK inhibitors (TKI) in patients with lung adenocarcinoma. In this study we evaluated the status of somatic mutations in the entire TK domain of the EGFR gene by direct sequencing using early passage peritoneal mesothelioma cells, established cell lines as well as 33 peritoneal mesothelioma tumor samples. No novel mutations were found in the cell lines. Sequence analysis of the EGFR TK domain revealed the presence of a silent polymorphism (c.2607G → A, Q787Q) at exon 20 of both peritoneal mesothelioma cell lines as well as tumor specimens. The frequency of genotypes AA and GA was 42.8 and 57.2% in the cell lines and 33.3 and 57.6% in tumor specimens, respectively. The TKI erlotinib showed an IC50 in the range of 10-50 µM in five out of the seven cell lines with a GA genotype while all five cell lines with the AA genotype had an IC50 >50 µM. Of the 33 peritoneal mesothelioma tumor samples analyzed none had an EGFR TKI sensitizing mutation and only one specimen showed an earlier reported somatic mutation at codon 850 in exon 21 of the EGFR gene. Our data show that patients with peritoneal mesothelioma do not harbor somatic mutations in the EGFR TK domain that would make them sensitive to EGFR TKI.

In plain English

This was a laboratory study by researchers at the US National Cancer Institute (NCI). It looked for mutations in the EGFR gene region encoding the protein's tyrosine kinase domain, the target of drugs called tyrosine kinase inhibitors, such as erlotinib. The authors sequenced this whole region (exons 18 to 24) in 14 peritoneal mesothelioma cell lines and 33 archived NCI tumor samples. The cell lines were 8 early cultures from patients' abdominal fluid and 6 established lines. The study did not examine asbestos exposure. No mutations were found in the cell lines. None of the 33 tumors had a mutation known to make tumors sensitive to these drugs. One tumor had a mutation, H850Y, at a position where different changes had been reported in other cancers. A common silent gene variant in exon 20 was frequent in cell lines and tumors. In dish tests, 5 of 7 tested cell lines carrying one copy of this variant were moderately sensitive to erlotinib, at doses the authors called not clinically relevant. All 5 tested lines carrying two copies were resistant. The authors concluded that these drugs will not be useful for treating peritoneal mesothelioma.

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 study: direct DNA sequencing of the EGFR tyrosine kinase domain (exons 18-24) in cell cultures, cell lines and archival tumor samples, plus erlotinib growth-inhibition tests on the cells
• Who was studied: 14 peritoneal mesothelioma cell lines: 8 early-passage cultures established at the NCI from patients' ascites, and 6 established lines. Also 33 archival peritoneal mesothelioma tumor samples from NCI patients (23 male, 10 female), all of epithelial histology. Of these patients, 25 had cytoreductive surgery with intraperitoneal hyperthermic chemotherapy and 8 had exploratory laparotomy.
• Exposure: Asbestos exposure was not studied. In the laboratory, the cells were exposed to the tyrosine kinase inhibitor erlotinib at 0.1 to 100 micromolar for 72 hours.
• Main results:
  • No mutations were found in the EGFR tyrosine kinase domain of the peritoneal mesothelioma cell lines.
  • Every cell line carried the silent exon 20 variant (c.2607G to A, Q787Q): 57.2% in the heterozygous GA form and 42.8% in the homozygous AA form.
  • Of the tested cell lines with the GA genotype, 5 out of 7 showed moderate sensitivity to erlotinib (IC50 less than 50 micromolar). The authors noted that these doses were not in the clinically relevant range.
  • Cell lines with the homozygous AA genotype were completely resistant to erlotinib (IC50 greater than 50 micromolar).
  • The authors reported no correlation between EGFR protein expression in the cell lines and their sensitivity to erlotinib. They did not show these data.
  • Only one of the 33 tumor samples had a mutation: H850Y, at codon 850 in exon 21. No other previously reported or novel EGFR mutations were found.
  • Mutations at codon 850 had been reported before in other cancers, but with a different amino-acid change from the H850Y found in this study.
  • For the exon 20 variant in the tumor samples, the text reports AA in 11 of 33 (33.3%), AG in 19 (57.6%) and GG in 3 (9.1%).
• The authors' conclusion: The authors concluded that sequencing of the entire EGFR tyrosine kinase domain found no sensitizing mutations, and that EGFR tyrosine kinase inhibitors will not be useful for treating patients with peritoneal mesothelioma.

Topics

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

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Tyrosine Kinase Inhibitor, EGFR, Somatic Mutation, Lung Adenocarcinoma.

Related studies

• Epidermal growth factor receptor mutations in malignant pleural and peritoneal mesothelioma — Y. Enomoto, T. Kasai, et al. (2012)
• Pulmonary adenocarcinoma with epidermal growth factor receptor-mutations in asbestos exposed non-smokers: A case series — R.L. Kradin, J. Iafrate, et al. (2017)
• Epidermal growth factor receptor mutations in 510 Finnish non--small-cell lung cancer patients — S. Mäki-Nevala, M. Rönty, et al. (2014)
• Coactivation of receptor tyrosine kinases in malignant mesothelioma as a rationale for combination targeted therapy — M. Brevet, S. Shimizu, et al. (2011)
• A comparison of epidermal growth factor receptor expression in malignant peritoneal and pleural mesothelioma — Y. Enomoto, T. Kasai, et al. (2012)
• Targeted inhibition of multiple receptor tyrosine kinases in mesothelioma — W.B. Ou, C. Hubert, et al. (2011)

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