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Poster display session

1014 - DS-1205b, a novel, selective, small-molecule inhibitor of AXL, delays the onset of resistance and overcomes acquired resistance to EGFR-TKIs in a human EGFR-mutant NSCLC (T790M-negative) xenograft model

Date

11 Sep 2017

Session

Poster display session

Presenters

Takeshi Jimbo

Citation

Annals of Oncology (2017) 28 (suppl_5): v122-v141. 10.1093/annonc/mdx367

Authors

T. Jimbo1, T. Taira1, T. Komatsu1, K. Kumazawa2, N. Maeda1, N. Haginoya1, T. Suzuki3, M. Ota4, Y. Totoki5, C. Wada5, K. Inaki5, T. Isoyama1, M. Uno1

Author affiliations

  • 1 Oncology Function, Daiichi Sankyo Co., LTD, 140-8710 - Tokyo/JP
  • 2 Quality & Safety Management Division, Daiichi Sankyo Co., LTD, Tokyo/JP
  • 3 Biologics Division, Daiichi Sankyo Co., LTD, 140-8710 - Tokyo/JP
  • 4 Research Management Department, Daiichi Sankyo RD Novare Co., LTD, Tokyo/JP
  • 5 Discovery Science And Technology Department, Daiichi Sankyo RD Novare Co., LTD, Tokyo/JP
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Resources

Abstract 1014

Background

AXL is a receptor tyrosine kinase that plays an important role in signal transduction in normal and malignant cells. Abnormal expression and/or activation of AXL can provide a survival advantage for certain cancer cells, and AXL up-regulation is associated with poor prognosis in several cancers. Recently, it has been reported that up-regulation of AXL expression is a mechanism of EGFR-TKI resistance in EGFR-mutant non-small cell lung cancer.

Methods

Kinase activity was measured by mobility shift assay. The inhibition of hGAS6-induced migration was measured in AXL-transfected NIH3T3 (NIH3T3-AXL) cells. The in vivo anti-tumor effects of DS-1205b mono- and combination-therapy with EGFR-TKI were evaluated in NIH3T3-AXL allograft and HCC827 xenograft models. Protein expression was analyzed by Western blot or immunohistochemistry and gene expression was analyzed by RT-PCR or RNA seq.

Results

We found that DS-1205b selectively inhibited AXL kinase activity with IC50 of 1.3 nM, and with NIH3T3-AXL cells, DS-1205b potently inhibited the hGAS6-induced migration in vitro with EC50 of 2.7 nM. DS-1205b monotherapy exerted significant antitumor activity in an NIH3T3-AXL allograft model. In an HCC827 xenograft model, combination treatment with DS-1205b and osimertinib significantly delayed on the onset of tumor resistance compared to osimertinib alone in a manner proportional to DS-1205b does. DS-1205b also showed a similar resistance delay effect with erlotinib combination in the same xenograft model. AXL up-regulation was associated with the development of resistance to erlotinib treatment in another HCC827 xenograft study, and DS-1205b restored the antitumor activity of erlotinib in erlotinib-resistant tumors in a dose-dependent manner.

Conclusions

In an HCC827 xenograft model of EGFR-mutant NSCLC, inhibition of AXL activity by DS-1205b restored sensitivity to erlotinib, and addition of DS-1205b to osimertinib delayed the onset of resistance to osimertinib. These findings support further non-clinical and clinical studies targeting inhibition of AXL in EGFRm NSCLC.

Clinical trial identification

Legal entity responsible for the study

Daiichi Sankyo Co., Ltd.

Funding

Daiichi Sankyo Co., Ltd.

Disclosure

T. Jimbo, T. Taira, T. Komatsu, K. Kumazawa, N. Maeda, N. Haginoya, T. Suzuki, M. Ota, Y. Totoki, C. Wada, K. Inaki, T. Isoyama, M. Uno: All authors are employees of Daiichi Sankyo Group which is developing DS-1205c.

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