Effects of Combined Therapeutic Targeting of AXL and ATR on Pleural Mesothelioma Cells

Our plain-English summary of Effects of Combined Therapeutic Targeting of AXL and ATR on Pleural Mesothelioma Cells, by S. Hirai, T. Yamada, Y. Katayama, et al (Molecular Cancer Therapeutics, 2024).

The study

• Authors: S. Hirai, T. Yamada, Y. Katayama, M. Ishida, H. Kawachi, Y. Matsui, R. Nakamura, K. Morimoto, M. Horinaka, T. Sakai, Y. Sekido, S. Tokuda, K. Takayama
• Journal: Molecular Cancer Therapeutics
• Published: 2024;23(2):212-222
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Few treatment options exist for pleural mesothelioma (PM), which is a progressive malignant tumor. However, the efficacy of molecular-targeted monotherapy is limited, and further therapeutic strategies are warranted to treat PM. Recently, the cancer cell-cycle checkpoint inhibitors have attracted attention because they disrupt cell-cycle regulation. Here, we aimed to establish a novel combinational therapeutic strategy to inhibit the cell-cycle checkpoint kinase, ATR in PM cells. The siRNA screening assay showed that anexelekto (AXL) knockdown enhanced cell growth inhibition when exposed to ATR inhibitors, demonstrating the synergistic effects of the ATR and AXL combination in some PM cells. The AXL and ATR inhibitor combination increased cell apoptosis via the Bim protein and suppressed cell migration when compared with each monotherapy. The combined therapeutic targeting of AXL and ATR significantly delayed regrowth compared with monotherapy. Thus, optimal AXL and ATR inhibition may potentially improve the PM outcome.

©2023 The Authors; Published by the American Association for Cancer Research.

In plain English

This laboratory study tested whether two experimental drugs together could slow the growth of pleural mesothelioma cells. No patients or asbestos exposures were studied. The authors tested an ATR inhibitor (AZD6738) and an AXL inhibitor (ONO7475) on 14 pleural mesothelioma cell lines. A gene-silencing screen suggested that blocking AXL made the ATR inhibitor work better. The combination reduced cell viability significantly more than either drug alone in 9 of the 14 cell lines, but not in the other five. It met the authors' measure of synergy in 6 of the 14. In immortalized normal mesothelial cells (Met-5A), the two drugs were antagonistic. In three cell lines, the combination reduced cell migration and increased cell death, which the authors linked to the protein Bim. In mice with tumors grown from one cell line, the combination significantly slowed tumor growth after day 31 and reduced tumor weight compared with either drug alone, without severe weight loss. The authors concluded this approach may potentially improve outcomes for patients. They noted that they found no predictive biomarkers and used only one cell line in mice.

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 (preclinical) study using human pleural mesothelioma cell lines and a mouse xenograft model
• Who was studied: 14 pleural mesothelioma cell lines (epithelial, biphasic and sarcomatoid types) and one immortalized normal mesothelial cell line (Met-5A). Tumors grown from the Y30 cell line were implanted under the skin of male SCID mice. The study was done at Kyoto Prefectural University of Medicine, Japan.
• Exposure: Drug treatments, not asbestos: AZD6738 (an ATR inhibitor), ONO7475 (an AXL and MER inhibitor), NPS1034 (an AXL and MET inhibitor), and gene silencing (siRNA) of AXL, ATR and Bim. In mice the doses were 25 mg/kg AZD6738 and 10 mg/kg ONO7475, given daily by mouth.
• Main results:
  • In a screen of 56 receptor tyrosine kinase siRNAs in H2373 and Y30 cells treated with AZD6738, the authors focused on AXL because silencing it reduced cell viability.
  • The AZD6738 plus ONO7475 combination produced a significant difference in viability compared with either drug alone in 9 of the 14 pleural mesothelioma cell lines.
  • In the other five cell lines, the combination was not significantly different from either drug alone.
  • Combination index values below 0.8, indicating synergy, were found for 6 of the 14 cell lines.
  • In immortalized normal mesothelial cells (Met-5A), the combination index was more than 1.2, indicating antagonism.
  • In H226, H2373 and Y30 cells, the combination significantly reduced the number of migrating cells compared with the AXL inhibitor alone.
  • The combination significantly increased apoptosis (programmed cell death) in H226, H2373 and Y30 cells compared with either drug alone.
  • Silencing Bim reduced caspase-3/7 activity (a measure of cell death) under the combination treatment.
  • In mice with Y30 tumors, the combination significantly inhibited tumor growth after day 31 compared with either drug alone.
  • At day 38, tumor weight in the combination group was significantly reduced compared with either drug alone.
  • Ki-67-positive (proliferating) tumor cells were significantly fewer with the combination than with either drug alone.
  • TUNEL-positive (apoptotic) tumor cells in mice did not differ significantly between the treatment groups.
  • No severe body weight loss was seen in treated mice, which the authors took to mean the combination was well tolerated.
• The authors' conclusion: The authors concluded that combined AXL and ATR inhibition had synergistic effects in some pleural mesothelioma cell lines. They concluded that optimal AXL and ATR inhibition may potentially improve the outcome of patients with pleural mesothelioma.
• Limitations the authors state:
  • The authors could not identify any factors usable as predictive biomarkers of response.
  • The authors found no apparent correlation between AXL and ATR-related protein levels and how well the combination worked.
  • The mouse tumor model used only one pleural mesothelioma cell line.
  • It is unclear whether the drug doses used in mice are suitable for using the drugs together.
  • The safety of the combination needs to be evaluated in clinical studies.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, checkpoint inhibitors, Synergistic Effect, Apoptosis.

Related studies

• The therapeutic efficacy of S-1 against orthotopically implanted human pleural mesothelioma cells in severe combined immunodeficient mice — T.T. Van, M. Hanibuchi, et al. (2011)
• Increasing the therapeutic index of 5-fluorouracil and 6-thioguanine by targeting loss of MTAP in tumor cells — B. Tang, J.R. Testa, et al. (2012)
• Multipoint targeting of the PI3K/mTOR pathway in mesothelioma — S. Zhou, L. Liu, et al. (2014)
• Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells — K. Kawaguchi, H. Murakami, et al. (2009)
• Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype — B. Zhong, M. Shingyoji, et al. (2020)
• Synergistic targeting of malignant pleural mesothelioma cells by MDM2 inhibitors and TRAIL agonists — L. Urso, I. Cavallari, et al. (2017)

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