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|Ref Type||Journal Article|
|Authors||Weisberg E, Kung AL, Wright RD, Moreno D, Catley L, Ray A, Zawel L, Tran M, Cools J, Gilliland G, Mitsiades C, McMillin DW, Jiang J, Hall-Meyers E, Griffin JD|
|Title||Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||Members of the inhibitor of apoptosis protein (IAP) family play a role in mediating apoptosis. Studies suggest that these proteins may be a viable target in leukemia because they have been found to be variably expressed in acute leukemias and are associated with chemosensitivity, chemoresistance, disease progression, remission, and patient survival. Another promising therapeutic target, FLT3, is mutated in about one third of acute myelogenous leukemia (AML) patients; promising results have recently been achieved in clinical trials investigating the effects of the protein tyrosine kinase inhibitor PKC412 on AML patients harboring mutations in the FLT3 protein. Of growing concern, however, is the development of drug resistance resulting from the emergence of point mutations in targeted tyrosine kinases used for treatment of acute leukemia patients. One approach to overriding resistance is to combine structurally unrelated inhibitors and/or inhibitors of different signaling pathways. The proapoptotic IAP inhibitor, LBW242, was shown in proliferation studies done in vitro to enhance the killing of PKC412-sensitive and PKC412-resistant cell lines expressing mutant FLT3 when combined with either PKC412 or standard cytotoxic agents (doxorubicin and Ara-c). In addition, in an in vivo imaging assay using bioluminescence as a measure of tumor burden, a total of 12 male NCr-nude mice were treated for 10 days with p.o. administration of vehicle, LBW242 (50 mg/kg/day), PKC412 (40 mg/kg/day), or a combination of LBW242 and PKC412; the lowest tumor burden was observed in the drug combination group. Finally, the combination of LBW242 and PKC412 was sufficient to override stromal-mediated viability signaling conferring resistance to PKC412.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|FLT3||A627T||missense||unknown||FLT3 A627T lies within the protein kinase domain of the Flt3 protein (UniProt.org). A627T has been identified as a drug resistance mutation (PMID: 15374944, PMID: 17620426), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Jun 2022).||Y|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|FLT3 exon 14 ins FLT3 A627T||hematologic cancer||predicted - resistant||Midostaurin||Preclinical - Cell culture||Actionable||In a preclinical study, transformed cells expressing a FLT3-ITD mutation with FLT3 A627T demonstrated resistance to Rydapt (midostaurin) in culture (PMID: 17620426).||17620426|