ONO-7475, a Novel AXL Inhibitor, Suppresses the Adaptive Resistance to Initial EGFR-TKI Treatment inEGFR-Mutated Non–Small Cell Lung Cancer

Abstract

Purpose: Currently, an optimal therapeutic strategy comprising molecularly targeted agents for treating EGFR-mutated non-small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib is not available. Therefore, the initial therapeutic intervention is crucial for the prolonged survival of these patients. The activation of anexelekto (AXL) signaling is known to be associated with intrinsic and acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study, we investigated the best therapeutic strategy to combat AXL-induced tolerance to EGFR-TKIs using the novel AXL inhibitor ONO-7475.Experimental Design: We examined the efficacy of ONO-7475 in combination with EGFR-TKIs in EGFR-mutated NSCLC cells using in vitro and in vivo experiments. We investigated the correlation between AXL expression in tumors and clinical outcomes with osimertinib for EGFR-mutated NSCLC patients with acquired resistance to initial EGFR-TKIs.Results: ONO-7475 sensitized AXL-overexpressing EGFRmutant NSCLC cells to the EGFR-TKIs osimertinib and dacomitinib. In addition, ONO-7475 suppressed the emergence and maintenance of EGFR-TKI-tolerant cells. In the cell line-derived xenograft models of AXL-overexpressing EGFR-mutated lung cancer treated with osimertinib, initial combination therapy of ONO-7475 and osimertinib markedly regressed tumors and delayed tumor regrowth compared with osimertinib alone or the combination after acquired resistance to osimertinib. AXL expression in EGFR-TKI refractory tumors did not correlate with the sensitivity of osimertinib.Conclusions: These results demonstrate that ONO-7475 suppresses the emergence and maintenance of tolerant cells to the initial EGFR-TKIs, osimertinib or dacomitinib, in AXL-overexpressing EGFR-mutated NSCLC cells, suggesting that ONO-7475 and osimertinib is a highly potent combination for initial treatment.

Identification of Hub Genes and Small Molecule Drugs Associated with Acquired Resistance to Gefitinib in Non-Small Cell Lung Cancer

“…However, the role of AXL in drug resistance remains unclear, the underlying mechanism may be related to the combination of AXL and other receptor tyrosine kinases (RTKs, including EGFR, ErbB receptor family members, MET and PDFGR) to promote EGFR-induced signaling into downstream 30 , 33 , there are also reports that the expression changes of AXL are highly relevant to the occurrence of epithelial-mesenchymal transition (EMT) 31 , 34 . The current research results of combination treatment of AXL inhibitors and EGFR TKIs in NSCLC indicate that AXL is a new target for reversing drug resistance 35 , 36 , and AXL small molecule inhibitors are also under development and testing. PNPLA4 plays an important role in catalyzing the hydrolysis of triglycerides and the metabolism of retinol-ester in the body 37 .…”

Emerging role of tumor cell plasticity in modifying therapeutic response

“…The therapeutic strategy of pharmacologically cotargeting YAP/TEAD (by MYF-01-37) and EGFR/MEK leads to synthetic lethality. AXL anexelekto, GAS6 growth arrest-specific protein 6, SGI-7079/XL-880 AXL inhibitor, EGF816 the third-generation EGFR-TKIs, FGFR1 fibroblast growth factor receptor 1, BGJ398: FGFR inhibitor is expected to be an effective therapeutic strategy for delaying or overcoming resistance in EGFR-mutant NSCLC, as seen in both in vitro and in vivo experimental models [440][441][442][443] (Fig. 3b).…”

“… 440 Interestingly, consistent with the above mechanism, the GAS6/AXL axis plays a vital role both in the development of de novo resistance to osimertinib and also in the initiation and maintenance of a “persistent” state from EMT induction with or without re-activation of HER3 and EGFR. 440 , 441 Therefore, the combination of the AXL inhibitor (Cabo or NPS1034) or the AXL degrader (Yuanhuadine, YD) with osimertinib is expected to be an effective therapeutic strategy for delaying or overcoming resistance in EGFR-mutant NSCLC, as seen in both in vitro and in viv o experimental models 440 – 443 (Fig. 3b ).…”

Targeting AXL in NSCLC

“… 42 For instance, a confluence of preclinical and translational data suggests that EGFR mutant patients receiving EGFR TKI may benefit from a combination with an AXL inhibitor. 73 , 74 …”