Combined Targeting of JAK2 and Bcl-2/Bcl-xL to Cure Mutant JAK2-Driven Malignancies and Overcome Acquired Resistance to JAK2 Inhibitors
Menée à l'aide de modèles murins, cette étude suggère l'intérêt d'une combinaison d'inhibiteurs de Bcl-2/Bcl-xL et de JAK2 pour surmonter une résistance à un inhibiteur de JAK2 seul dans le traitement d'une hématopathie maligne présentant une mutation activatrice de JAK2
To design rational therapies for JAK2-driven hematological malignancies, we functionally dissected the key survival pathways downstream of hyperactive JAK2. In tumors driven by mutant JAK2, Stat1, Stat3, Stat5, and the Pi3k and Mek/Erk pathways were constitutively active, and gene expression profiling of TEL-JAK2 T-ALL cells revealed the upregulation of prosurvival Bcl-2 family genes. Combining the Bcl-2/Bcl-xL inhibitor ABT-737 with JAK2 inhibitors mediated prolonged disease regressions and cures in mice bearing primary human and mouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was able to circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment. Thus, inhibiting the oncogenic JAK2 signaling network at two nodal points, at the initiating stage (JAK2) and the effector stage (Bcl-2/Bcl-xL), is highly effective and provides a clearly superior therapeutic benefit than targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2. "Bcl-2 and Bcl-xL are the key survival factors downstream of oncogenic JAK2 "Combined targeting of JAK2 and Bcl-2/Bcl-xL is highly efficacious in vivo "Combination therapy is well tolerated in preclinical models of JAK2-driven ALL "Combination therapy can overcome and circumvent resistance to JAK2 inhibitors Better therapeutic options are required for mutant JAK2-driven hemopoietic malignancies to overcome intrinsic and acquired therapy resistance. Johnstone and colleagues functionally dissect signaling pathways downstream of hyperactive JAK2 and define the STAT5-Bcl-2/Bcl-xL axis as crucial for tumor cell survival and development of acquired JAK inhibitor resistance. Combined inhibition of this oncogenic JAK2 signaling network at two critical points JAK2 and Bcl-2/Bcl-xL proved highly efficacious in vivo and was able to circumvent and overcome acquired resistance to single-agent JAK inhibitors.
http://linkinghub.elsevier.com/retrieve/pii/S2211124713006372