Research Papers:

DS-1205b, a novel selective inhibitor of AXL kinase, blocks resistance to EGFR-tyrosine kinase inhibitors in a non-small cell lung cancer xenograft model

Takeshi Jimbo, Mana Hatanaka, Takahiro Komatsu, Tomoe Taira, Kentaro Kumazawa, Naoyuki Maeda, Takashi Suzuki, Masahiro Ota, Noriyasu Haginoya, Takeshi Isoyama and Kosaku Fujiwara

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Oncotarget. 2019; 10:5152-5167. https://doi.org/10.18632/oncotarget.27114

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Takeshi Jimbo1, Mana Hatanaka1, Takahiro Komatsu1, Tomoe Taira1, Kentaro Kumazawa2, Naoyuki Maeda1, Takashi Suzuki3, Masahiro Ota4, Noriyasu Haginoya1, Takeshi Isoyama1 and Kosaku Fujiwara5

1 Oncology Function, Daiichi Sankyo Co., Ltd., Tokyo, Japan

2 Quality & Safety Management Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan

3 Biologics Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan

4 Research Management Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan

5 Medical Affairs Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan

Correspondence to:

Takeshi Jimbo,email: [email protected]

Keywords: AXL; DS-1205; EGFR-TKI resistance; erlotinib; osimertinib

Received: March 12, 2019     Accepted: June 29, 2019     Published: August 27, 2019


The AXL receptor tyrosine kinase is involved in signal transduction in malignant cells. Recent studies have shown that the AXL upregulation underlies epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) resistance in EGFR-mutant non-small cell lung cancer (NSCLC). In this study, we investigated the effect of DS-1205b, a novel and selective inhibitor of AXL, on tumor growth and resistance to EGFR TKIs. In AXL-overexpressing NIH3T3 cells, DS-1205b potently inhibited hGAS6 ligand-induced migration in vitro and exerted significant antitumor activity in vivo. AXL was upregulated by long-term erlotinib or osimertinib treatment in HCC827 EGFR-mutant NSCLC cells, and DS-1205b treatment in combination with osimertinib or erlotinib effectively inhibited signaling downstream of EGFR in a cell-based assay. In an HCC827 EGFR-mutant NSCLC xenograft mouse model, combination treatment with DS-1205b and erlotinib significantly delayed the onset of tumor resistance compared to erlotinib monotherapy, and DS-1205b restored the antitumor activity of erlotinib in erlotinib-resistant tumors. DS-1205b also delayed the onset of resistance when used in combination with osimertinib in the model. These findings strongly suggest that DS-1205b can prolong the therapeutic benefit of EGFR TKIs in nonclinical as well as clinical settings.

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