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

Molecular Cancer Therapeutics 2023 October 7 [Link]

Soichi Hirai, Tadaaki Yamada, Yuki Katayama, Masaki Ishida, Hayato Kawachi, Yohei Matsui, Ryota Nakamura, Kenji Morimoto, Mano Horinaka, Toshiyuki Sakai, Yoshitaka Sekido, Shinsaku Tokuda, Koichi Takayama


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, ataxia telangiectasia and Rad3-related protein (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 to 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.