EGFR tyrosine kinase inhibitors (EGFR-TKIs) are efficient for the treatment of non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, most EGFR-positive NSCLC patients exhibit resistance to EGFR-TKIs after sometimes. The 3rd generation EGFR-TKI Osimertinib shows efficacy for overcoming EGFR T790M mutation-positive NSCLC.
Anexelekto (AXL) belongs to the TAM family of proteins. AXL usually expresses in epithelial and mesenchymal cells, it also expresses in breast, pancreatic, lung, and bone marrow cancers. This kinase in tumors plays an important role in contributing to proliferation, migration, and survival. The regulation of the AXL pathway is a promising therapeutic strategy against malignant progress in EGFR-related cancers.
Hence, in this article, we will introduce a potent, selective, and orally active novel Anexelekto (AXL)/Mer inhibitor, ONO-7475.
We will concisely introduce this potent inhibitor in vitro and in vivo.
Firstly, ONO-7475 increases the sensitivity to Osimertinib and Dacomitinib and reduces the viability of high AXL-expressing PC-9 and HCC4011 cells, but has no effects on low-AXL-expressing HCC827 cells.
Besides, ONO-7475 enhances Osimertinib efficacy on the viability of cell lines PC-9, PC-9KGR, and HCC4011, and H1975, all of which express high levels of AXL. However, it has a marginal effect on the viability of cell lines HCC827, HCC4006, and H3255 with low levels of AXL.
Nextly, When it compares with the treatment of the high-AXL-expressing cell lines treated with Osimertinib alone. ONO-7475 combines with Osimertinib can markedly inhibit the phosphorylation of AXL, AKT, and p70S6K. Additionally, the Combination with Osimertinib increases cleaved-PARP in PC-9 and HCC4011 cells.
Lastly, in the CDX mice model using high-AXL-expressing PC-9KGR cells. ONO-7475 oral gavage alone has little effect on tumor growth. Besides, Osimertinib alone causes tumor regression within one week, but the tumors reappear within three weeks. However, the combined initial treatment causes tumor regression and the size of tumors maintains for 4 weeks. Moreover, No apparent adverse events, including weight loss appears during this treatment.
In conclusion, ONO-7475 is a potent, selective, and orally active novel Anexelekto (AXL) inhibitor. It against recombinant human AXL with IC50 values of 0.414 nM and 0.7 nM in off-chip MSA and ACD cell-based tyrosine kinase assay, respectively. ONO-7475 sensitizes AXL-overexpressing GFP-mutant NSCLC cells to the EGFR-TKIs, suppresses the emergence and maintenance of tolerant cells. ONO-7475 combines with Osimertinib provides a bright promise for the study of EGFR-mutated non-small cell lung cancer.
Reference:
Okura N, et al. Clin Cancer Res. 2020 Jan 17.