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N. Haginoya
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-042 - DS-1205b, a Novel, Selective, Inhibitor of AXL, Delays the Onset of Resistance and Overcomes Acquired Resistance to EGFR-TKIs (ID 9174)
09:30 - 09:30 | Author(s): N. Haginoya
- Abstract
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 represents a mechanism of EGFR-TKI resistance in EGFR-mutant non-small cell lung cancer.
Method:
Kinase activity was measured by mobility shift assay. The inhibition of hGAS6-induced migration was measured in AXL-transfected NIH3T3 (NIH3T3-AXL) cells using a real-time cell analyzer (RTCA) DP instrument. The in vivo anti-tumor effects of DS-1205b mono- and combination-therapy with EGFR-TKI were evaluated in NIH3T3-AXL allograft and EGFR-mutant NSCLC (T790M-negative) HCC827 xenograft models. Protein expression was analyzed by Western blot or immunohistochemistry, and gene expression was analyzed by RT-PCR or RNA seq.
Result:
DS-1205b selectively inhibited AXL kinase activity with IC~50~ of 1.3 nM, and with NIH3T3-AXL cells, DS-1205b inhibited hGAS6-induced migration in vitro with EC~50~ of 2.7 nM. DS-1205b monotherapy exerted significant antitumor activity including tumor regression 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 dose. DS-1205b also showed a similar resistance delay effect in combination with erlotinib or gefitinib in the same xenograft model. AXL up-regulation was associated with the development of resistance to erlotinib or gefitinib treatment in another HCC827 xenograft study, and DS-1205b restored the antitumor activity of erlotinib in erlotinib-resistant tumors in a dose-dependent manner. Combination treatment of DS-1205b with osimertinib, erlotinib, or gefitinib delayed the onset of resistance in acquired-resistance models using HCC827, and among these three models, the delay of resistance onset with DS-1205b was observed to be greatest in the osimertinib model. AXL and some EMT-related genes were up-regulated in EGFR-TKI-resistant tumors, while cell cycle, migration, or angiogenesis factors were down-regulated by treatment of those tumors with combination of DS-1205b and EGFR-TKI.
Conclusion:
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. A phase I study in combination with osimertinib is ongoing, and its design is shown in a separate presentation.
