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Ref Type Journal Article
PMID (24553136)
Authors Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP, Cronin SJ, Nitsch R, Schultz-Fademrecht C, Eickhoff J, Menninger S, Unger A, Torka R, Gruber T, Hinterleitner R, Baier G, Wolf D, Ullrich A, Klebl BM, Penninger JM
Title The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells.
Journal Nature
Vol 507
Issue 7493
Date 2014 Mar 27
URL
Abstract Text Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy. New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies. Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology. This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.

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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
LDC1267 LDC1267 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
LDC1267 AXL Inhibitor 27 MERTK Inhibitor 9 TYRO3 Inhibitor 8 LDC1267 is a specific TAM kinase inhibitor, with activity against TYRO3, AXL, and MERTK, which potentially enhances anti-tumor immune response and decreases tumor metastasis (PMID: 24553136).
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
Unknown unknown melanoma not applicable LDC1267 Preclinical Actionable In a preclinical study, LDC1267 treatment resulted in decreased metastasis in a mouse model of metastatic melanoma (PMID: 24553136). 24553136
Unknown unknown breast cancer not applicable LDC1267 Preclinical Actionable In a preclinical study, LDC1267 treatment resulted in reduced l metastatic liver lesions, but did not impact primary tumor growth, in a mouse model of metastatic breast cancer (PMID: 24553136). 24553136