In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3804-3804
Abstract:
Lung cancer is the leading cause of cancer related death in the US (2017). Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancer cases. While EGFR inhibitors (EGFRi) have shown activity in NSCLC, single agent response rates often do not exceed 10%. EGFR mutation is a common oncogenic driver in NSCLC, appearing in between 13% and 47% of all NSCLC patients depending on ethnicity. Third generation EGFRis, such as osimertinib, were approved upon demonstrating improved progression-free survival (PFS) rates versus standard therapy. However, EGFR inhibitor resistance, including resistance to osimertinib, has been reported to result from the epithelial-to-mesenchymal transition (EMT) that is coincident with increased AXL kinase expression. The AXL RTK drives EMT and constitutes a bypass survival pathway for tumor cells under EGFRi treatment pressure. We have shown that treatment with TP-0903, our potent AXL inhibitor, leads to a reversal of the mesenchymal phenotype in multiple cancer models. We therefore hypothesized that TP-0903 treatment may potentiate EGFRi treatment in cancer, and in particular EGFR mutant NSCLC. To interrogate our hypothesis, we treated cells with TP-0903 and assessed changes in cell viability with the celltiter-glo assay, changes in mRNA expression using RT-qPCR, and protein expression changes, using standard immunoblotting. In cell viability assays in the H1650 NSCLC cell line, TP-0903 showed an EC50 of 39 nM, while osimertinib showed an EC50 of 2.2 µM. In mRNA and protein assays, we observed changes consistent with a reversal of the mesenchymal phenotype. Following treatment, Slug mRNA expression was inhibited as much as 3.8-fold. However, E-cadherin expression was increased by 1.6-fold. To assess the combination in vivo, we utilized the H1650 xenograft model for NSCLC. In pharmacodynamic assessment of EMT markers in vivo, Snail protein expression was reduced as much as 56% following a single dose of TP-0903 (40 mpk, at 24hrs). In assessment of treatment efficacy in vivo, and with TP-0903 treatment (40 mpk, qd), we observed 60% tumor growth inhibition (%TGI) over the course of a 21-day treatment regimen. With osimertinib treatment (20 mpk, qd), we observed 121 %TGI. However, with the combination, we observed 140 %TGI. Due to its ability to reverse the aggressive mesenchymal phenotype of cancer cells, TP-0903 is a promising agent with the potential to have single agent activity and combined synergy with targeted anti-cancer agents. A Phase I trial with this investigational agent is ongoing, which includes patients with EGFR positive non-small cell lung cancer (clincaltrials.gov, NCT02729298). Taken together, the current study supports continued development of AXL inhibitors in NSCLC, especially in combination with EGFRis. Citation Format: Ryan Mangelson, Ethika Tyagi, Peter Peterson, Adam Siddiqui-Jain, Clifford J. Whatcott, David J. Bearss, Steven L. Warner. The potent AXL kinase inhibitor, TP-0903, is active in pre-clinical models of EGFR positive non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3804.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2019-3804
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2019
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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