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|Ref Type||Journal Article|
|Authors||Murone M, Vaslin Chessex A, Attinger A, Ramachandra R, Shetty SJ, Daginakatte G, Sengupta S, Marappan S, Dhodheri S, Rigotti S, Bachhav Y, Brienza S, Traxler P, Lang M, Aguet M, Zoete V, Michielin O, Nicholas C, Johnson FM, Ramachandra M, McAllister A|
|Title||Debio 0617B Inhibits Growth of STAT3-Driven Solid Tumors through Combined Inhibition of JAK, SRC, and Class III/V Receptor Tyrosine Kinases.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||Tumor survival, metastases, chemoresistance, and escape from immune responses have been associated with inappropriate activation of STAT3 and/or STAT5 in various cancers, including solid tumors. Debio 0617B has been developed as a first-in-class kinase inhibitor with a unique profile targeting phospho-STAT3 (pSTAT3) and/or pSTAT5 in tumors through combined inhibition of JAK, SRC, ABL, and class III/V receptor tyrosine kinases (RTK). Debio 0617B showed dose-dependent inhibition of pSTAT3 in STAT3-activated carcinoma cell lines; Debio 0617B also showed potent antiproliferative activity in a panel of cancer cell lines and in patient-derived tumor xenografts tested in an in vitro clonogenic assay. Debio 0617B showed in vivo efficacy by inhibiting tumor growth in several mouse xenograft models. To increase in vivo efficacy and STAT3 inhibition, Debio 0617B was tested in combination with the EGFR inhibitor erlotinib in a non-small cell lung cancer xenograft model. To evaluate the impact of in vivo STAT3 blockade on metastases, Debio 0617B was tested in an orthotopic tumor model. Measurement of primary tumor weight and metastatic counts in lung tissue demonstrated therapeutic efficacy of Debio 0617B in this model. These data show potent activity of Debio 0617B on a broad spectrum of STAT3-driven solid tumors and synergistic activity in combination with EGFR inhibition. Mol Cancer Ther; 15(10); 2334-43. ©2016 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Debio 0617B||ABL Inhibitor (pan) 8 CSF1R Inhibitor 24 FLT3 Inhibitor 55 JAK Inhibitor (Pan) 8 KIT Inhibitor 51 PDGFR Inhibitor (Pan) 27 SRC Inhibitor 29 VEGFR Inhibitor (Pan) 32||Debio 0617B is a multi-kinase inhibitor of SRC, JAK, and ABL, the class III kinases, CSF1R, FLT3, KIT, and PDGFR, and the class V kinases, VEGFR 1/2/3, which may result in inhibition of Stat3 and Stat5 signaling, leading to inhibition of tumor cell growth and metastasis (PMID: 27439479, PMID: 28468777).|
|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||Advanced Solid Tumor||not applicable||Debio 0617B||Preclinical - Patient cell culture||Actionable||In a preclinical study, Debio 0617B inhibited survival of a variety of patient-derived tumor cells in culture (PMID: 27439479).||27439479|