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Ref Type Journal Article
PMID (36279567)
Authors Tsukamoto S, Sugi NH, Nishibata K, Nakazawa Y, Ito D, Fukushima S, Nakagawa T, Ichikawa K, Kato Y, Kakiuchi D, Goto A, Itoh-Yagi M, Aota T, Inoue S, Yamane Y, Murai N, Azuma H, Nagao S, Sasai K, Akagi T, Imai T, Matsui J, Matsushima T
Title ER-851, a Novel Selective Inhibitor of AXL, Overcomes Resistance to Antimitotic Drugs.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 22 1 2023 Jan 03 12-24 Mol Cancer Ther
URL
Abstract Text Innate and adaptive resistance to cancer therapies, such as chemotherapies, molecularly targeted therapies, and immune-modulating therapies, is a major issue in clinical practice. Subpopulations of tumor cells expressing the receptor tyrosine kinase AXL become enriched after treatment with antimitotic drugs, causing tumor relapse. Elevated AXL expression is closely associated with drug resistance in clinical samples, suggesting that AXL plays a pivotal role in drug resistance. Although several molecules with AXL inhibitory activity have been developed, none have sufficient activity and selectivity to be clinically effective when administered in combination with a cancer therapy. Here, we report a novel small molecule, ER-851, which is a potent and highly selective AXL inhibitor. To investigate resistance mechanisms and identify driving molecules, we conducted a comprehensive gene expression analysis of chemoresistant tumor cells in mouse xenograft models of genetically engineered human lung cancer and human triple-negative breast cancer. Consistent with the effect of AXL knockdown, cotreatment of ER-851 and antimitotic drugs produced an antitumor effect and prolonged relapse-free survival in the mouse xenograft model of human triple-negative breast cancer. Importantly, when orally administered to BALB/c mice, this compound did not induce retinal toxicity, a known side effect of chronic MER inhibition. Together, these data strongly suggest that AXL is a therapeutic target for overcoming drug resistance and that ER-851 is a promising candidate therapeutic agent for use against AXL-expressing antimitotic-resistant tumors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
ER-851 ER-851 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
ER-851 ER-001259851-000|ER851|ER 851 AXL Inhibitor 30 ER-851 selectively inhibits AXL, potentially leading to decreased cell viability and reduced of tumor growth (PMID: 36279567).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References