Reference Detail

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-001259851-000, a novel selective inhibitor of AXL, overcomes resistance to antimitotic drugs.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics			2022 Oct 22	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 anti-mitotic 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-001259851-000, 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 chemo-resistant 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, co-treatment of ER-001259851-000 and antimitotic drugs produced an anti-tumor 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-001259851-000 is a promising candidate therapeutic agent for use against AXL-expressing anti-mitotic-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	1	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
AXL positive	Advanced Solid Tumor	sensitive	ER-851	Preclinical - Cell culture	Actionable	In a preclinical study, ER-851 decreased viability of transformed cells expressing AXL in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 36279567).	36279567