Lapatinib enhances trastuzumab-mediated antibody-dependent cellular cytotoxicity via upregulation of HER2 in malignant mesothelioma cells

Our plain-English summary of Lapatinib enhances trastuzumab-mediated antibody-dependent cellular cytotoxicity via upregulation of HER2 in malignant mesothelioma cells, by R. Okita, K. Shimizu, Y. Nojima, et al (Oncology Reports, 2015).

The study

• Authors: R. Okita, K. Shimizu, Y. Nojima, T. Yukawa, A. Maeda, S. Saisho, M. Nakata
• Journal: Oncology Reports
• Published: 2015;34(6):2864-70
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

EGFR/HER2 are frequently expressed in MPM tissues, however, no studies have shown the clinical benefit of using EGFR/HER2-targeting drugs in patients with malignant pleural mesothelioma (MPM). It was reported that the tyrosine kinase inhibitor (TKI) lapatinib enhanced trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) in HER2-positive breast cancer, suggesting that this combination is a promising strategy for MPM treatment. The aim of the present study was to explore the possibility of a TKI combined with trastuzumab to enhance ADCC in MPM cells. Five MPM cell lines were used to test the effects of TKIs targeting EGFR (gefitinib, afatinib and lapatinib) on cell proliferation and the expression of the HER family receptor. The combined effects of TKI with trastuzumab on ADCC were evaluated using the LDH release assay. Additionally, MPM cells were isolated from patients and evaluated for lapatinib-induced upregulation of HER family receptors and trastuzumab- or cetuximab‑mediated ADCC. In MPM cell lines, HER2 expression was upregulated by lapatinib, downregulated by afatinib and unaffected by gefitinib. As expected, more trastuzumab bound to MPM cells pretreated with lapatinib than untreated cells, resulting in the enhancement of trastuzumab-mediated ADCC in MPM cells. In patient-derived MPM cells, both HER2 and EGFR were upregulated by lapatinib, resulting in the enhancement of both trastuzumab- and cetuximab-mediated ADCC. Of the three TKIs, only lapatinib enhanced trastuzumab-mediated ADCC via the upregulation of HER2 expression in MPM cells, suggesting that sequential combination of lapatinib and trastuzumab may be a promising strategy for MPM treatment.

In plain English

This laboratory study from Kawasaki Medical School, Japan, examined malignant pleural mesothelioma cells grown in dishes. It did not treat patients or study asbestos exposure. The authors used five mesothelioma cell lines and cells from a malignant effusion (fluid build-up) of one patient. Tissue from three patients did not yield enough viable cells. The authors tested how three receptor-blocking drugs (gefitinib, afatinib and lapatinib) affected cell growth, receptor levels and receptor signaling. Using immune cells from healthy donors, they also tested two things. They tested whether afatinib or lapatinib pretreatment helped the antibody trastuzumab kill two cell lines. They also tested whether lapatinib helped trastuzumab and cetuximab kill the patient's cells. Afatinib and lapatinib clearly slowed cell growth, while gefitinib had a slight effect. Lapatinib raised the amount of the receptor HER2 on all cell lines, while afatinib lowered it. In two cell lines, lapatinib increased trastuzumab-driven killing, and afatinib did not. In the patient's cells, in single experiments, lapatinib increased both kinds of killing. The text gives no numerical effect sizes, only significance levels in figure captions. The authors concluded that lapatinib is an ideal partner drug for these antibodies in mesothelioma treatment.

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 (in vitro) study of mesothelioma cell lines and patient-derived mesothelioma cells
• Who was studied: Five malignant pleural mesothelioma cell lines (NCI-H28, NCI-H2052, MSTO211, MESO1, MESO4) and mesothelioma cells (MPM-p3) from a malignant effusion of one patient, at Kawasaki Medical School, Japan. Tissue from three patients did not yield enough viable cells. Immune effector cells came from healthy donors.
• Exposure: No asbestos exposure was studied. For the growth tests, the cells were treated with the tyrosine kinase inhibitors gefitinib, afatinib and lapatinib at 0.01-10 µM. For the killing tests, only afatinib or lapatinib was used (1 µM for 24 h). This was followed by the antibodies trastuzumab or cetuximab (100 ng/ml), with rituximab as an irrelevant control.
• Main results:
  • Before treatment, EGFR was highly expressed in all mesothelioma cells, and HER2 was also expressed in all of them. HER3 expression was rare and low.
  • Afatinib and lapatinib clearly inhibited growth of the mesothelioma cells. Gefitinib had only a slight effect.
  • Lapatinib upregulated HER2 in all cell lines. Afatinib downregulated HER2 in all cell lines and downregulated EGFR in NCI-H28 and NCI-H2052.
  • Gefitinib had no effect on EGFR or HER2 expression in the cell lines or in the patient-derived MPM-p3 cells.
  • In NCI-H28 and NCI-H2052 cells, afatinib and lapatinib strongly and similarly inhibited activation (phosphorylation) of EGFR and HER2.
  • In two cell lines (NCI-H28 and NCI-H2052), lapatinib increased trastuzumab binding and enhanced trastuzumab-mediated killing compared with untreated (DMSO) cells. Afatinib did not enhance this killing.
  • In the patient-derived MPM-p3 cells, lapatinib increased both cetuximab and trastuzumab binding sites. It also enhanced both cetuximab- and trastuzumab-mediated killing. These were single experiments.
• The authors' conclusion: The authors concluded that lapatinib is an ideal partner drug for cetuximab or trastuzumab to enhance antibody-dependent cell killing for mesothelioma treatment. They also concluded that the sequential combination may be a promising strategy.

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: Trastuzumab, HER2, Malignant Mesothelioma, EGFR, Pleural Mesothelioma, Tyrosine Kinase Inhibitor, LDH Release, Cetuximab (Erbitux).

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