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Ref Type Journal Article
PMID (22784709)
Authors Anbalagan M, Ali A, Jones RK, Marsden CG, Sheng M, Carrier L, Bu Y, Hangauer D, Rowan BG
Title Peptidomimetic Src/pretubulin inhibitor KX-01 alone and in combination with paclitaxel suppresses growth, metastasis in human ER/PR/HER2-negative tumor xenografts.
Journal Molecular cancer therapeutics
Vol 11
Issue 9
Date 2012 Sep
URL
Abstract Text Src kinase is elevated in breast tumors that are ER/PR negative and do not overexpress HER2, but clinical trials with Src inhibitors have shown little activity. The present study evaluated preclinical efficacy of a novel peptidomimetic compound, KX-01 (KX2-391), that exhibits dual action as an Src and pretubulin inhibitor. KX-01 was evaluated as a single-agent and in combination with paclitaxel in MDA-MB-231, MDA-MB-157, and MDA-MB-468 human ER/PR/HER2-negative breast cancer cells. Treatments were evaluated by growth/apoptosis, isobologram analysis, migration/invasion assays, tumor xenograft volume, metastasis, and measurement of Src, focal adhesion kinase (FAK), microtubules, Ki67, and microvessel density. KX-01 inhibited cell growth in vitro and in combination with paclitaxel resulted in synergistic growth inhibition. KX-01 resulted in a dose-dependent inhibition of MDA-MB-231 and MDA-MB-157 tumor xenografts (1 and 5 mg/kg, twice daily). KX-01 inhibited activity of Src and downstream mediator FAK in tumors that was coincident with reduced proliferation and angiogenesis and increased apoptosis. KX01 also resulted in microtubule disruption in tumors. Combination of KX-01 with paclitaxel resulted in significant regression of MDA-MB-231 tumors and reduced metastasis to mouse lung and liver. KX-01 is a potently active Src/pretubulin inhibitor that inhibits breast tumor growth and metastasis. As ER/PR/HER2-negative patients are candidates for paclitaxel therapy, combination with KX-01 may potentiate antitumor efficacy in management of this aggressive breast cancer subtype.

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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
KX2-391 KX2-391 3 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
KX2-391 KX-01|Tirbanibulin SRC Inhibitor 29 Tirbanibulin (KX2-391) is a peptidomimetic dual inhibitor of Src and pretubulin, which inhibits SRC in a non-ATP-competitive manner, resulting in tumor growth inhibition and metastasis prevention (PMID: 22784709, PMID: 31628188).
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
SRC positive triple-receptor negative breast cancer sensitive KX2-391 + Paclitaxel Preclinical - Cell line xenograft Actionable In a preclinical study, KX2-392 and Taxol (paclitaxel) worked synergistically to inhibit Src signaling and proliferation of triple-receptor negative breast cancer cell lines in culture, and induced tumor regression and suppressed metastasis in xenograft models (PMID: 22784709). 22784709
SRC positive triple-receptor negative breast cancer sensitive KX2-391 Preclinical - Cell line xenograft Actionable In a preclinical study, KX2-392 inhibited Src signaling and proliferation in triple-receptor negative breast cancer cell lines in culture, and suppressed tumor growth in xenograft models (PMID: 22784709). 22784709