531P - Effect of combinational targeted therapy for AXL and ATR against malignant mesothelioma cells

Background

Few treatment options exist for malignant mesothelioma, which is a progressive malignant tumor. As for the systemic treatment, combination therapy with the cytotoxic anticancer drugs, cisplatin and pemetrexed, have been used to treat inoperable MM. However, the efficacy of molecular-targeted monotherapy is limited, and further therapeutic strategies are warranted to treat malignant mesothelioma. Recently, the cancer cell cycle checkpoint inhibitors have attracted attention because they disrupt cell cycle regulation, thereby causing lethality in tumor synthesis.

Methods

To evaluate the impact of ataxia telangiectasia and Rad3-related protein (ATR) inhibition in MM cells, we examined the efficacy of the ATR inhibitor AZD6738 on cell growth inhibition using 14 MM cell lines. Fifty-six receptor-type tyrosine kinase siRNAs were used to search for molecular targets that are highly effective in combination with ATR inhibitors. The combined effects of the found molecular inhibitors and ATR inhibitors were examined in 14 MM cell lines, and the molecular signals of the cell lines with the highest combined effects were examined by Western blotting, and apoptosis assays were performed using FACS. We examined the anti-tumor potential in the combination therapy using a cell line-derived xenograft (CDX) model.

Results

We aimed to establish a novel combination strategy to inhibit the cell cycle checkpoint kinase, ATR in malignant pleural mesothelioma 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 malignant mesothelioma cells. The AXL and ATR inhibitor combination increased cell apoptosis via the Bim protein, and suppressed cell migration, compared with the effects in each monotherapy. CDX models showed that this novel combination significantly attenuated tumor growth compared with each monotherapy.

Conclusions

Our observations showed that optimal AXL and ATR inhibition may potentially improve the outcome of patients with MM.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

This work was supported by research grants from Medical Research Continuous Grants of Takeda Science Foundation (to T. Yamada) and Research Grant of the Princess Takamatsu Cancer Research Fund (to T. Yamada).

Disclosure

T. Yamada: Financial Interests, Personal, Funding: Pfizer, Ono Pharmaceutical, Janssen Pharmaceutical K.K., AstraZeneca, Takeda Pharmaceutical Company. K. Takayama: Financial Interests, Personal, Funding: Chugai-Roche, Ono Pharmaceutical; Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai-Roche, MSD-Merck, Eli Lilly, Boehringer Ingelheim, Daiichi Sankyo. All other authors have declared no conflicts of interest.