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|Ref Type||Journal Article|
|Authors||Silveira AB, Laranjeira AB, Rodrigues GO, Leal PC, Cardoso BA, Barata JT, Yunes RA, Zanchin NI, Brandalise SR, Yunes JA|
|Title||PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia.|
|Date||2015 May 30|
|Abstract Text||The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. By gene expression microarray analysis of T-ALL cells treated with the PI3K inhibitor AS605240, we identified Myc as a prominent downstream target of the PI3K pathway. A significant association was found between the AS605240 gene expression signature and that of glucocorticoid resistance and relapse in T-ALL. AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy.|
|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|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||acute lymphoblastic leukemia||not applicable||AS605240 + Prednisolone||Preclinical - Cell culture||Actionable||In a preclinical study, AS605240 and prednisolone synergistically inhibited survival of T-acute lymphocytic leukemia cell lines in culture (PMID: 25869207).||25869207|
|Unknown unknown||acute lymphoblastic leukemia||not applicable||AS605240 + Dexamethasone||Preclinical - Pdx||Actionable||In a preclinical study, the combination of AS605240 and dexamethasone improved survival of primary T-ALL cell xenograft models (PMID: 25869207).||25869207|
|Unknown unknown||acute lymphoblastic leukemia||not applicable||AS605240||Preclinical - Pdx & cell culture||Actionable||In a preclinical study, AS605240 increased apoptosis and decreased viability of T-acute lymphocytic leukemia (T-ALL) cell lines and primary T-ALL cells in culture, and decreased leukemic progression in a primary T-ALL cell xenograft model (PMID: 25869207).||25869207|