Targeting Nonclassical Oncogenes for Therapy in T-ALL
Menée à l'aide d'un modèle murin, cette étude suggère que l'inhibition conjointe des isoformes gamma et delta de PI3K est une stratégie intéressante pour le traitement d'une leucémie aiguë lymphoblastique T
Constitutive phosphoinositide 3-kinase (PI3K)/Akt activation is common in T cell acute lymphoblastic leukemia (T-ALL). Although four distinct class I PI3K isoforms (±, ², ³, ´) could participate in T-ALL pathogenesis, none has been implicated in this process. We report that in the absence of PTEN phosphatase tumor suppressor function, PI3K³ or PI3K´ alone can support leukemogenesis, whereas inactivation of both isoforms suppressed tumor formation. The reliance of PTEN null T-ALL on the combined activities of PI3K³/´ was further demonstrated by the ability of a dual inhibitor to reduce disease burden and prolong survival in mice as well as prevent proliferation and promote activation of proapoptotic pathways in human tumors. These results support combined inhibition of PI3K³/´ as therapy for T-ALL. º Deregulation of PI3K³ or PI3K´ activity promotes leukemogenesis º Combined activities of PI3K³ and PI3K´ support the survival of PTEN null T-ALL º One can therapeutically exploit the addiction of T-ALL to PI3K³/PI3K´ º Data support PI3K³ and PI3K´ dual inhibitors as targeted therapy for T-ALL
Cancer cell , résumé, 2011