Activation and targeting of prosurvival pathways mediating FLT3 resistance. (A) The downstream effectors pERK, pAKt, pS6K, and pSTAT are not sufficiently inhibited despite FLT3 signaling blockade in sorafenib-resistant FLT3 cell lines harboring acquired point mutations in the tyrosine kinase domains. The MEK/ERK pathway likely plays a central role in this feedback modulation with smaller contributions from the PI3K/AKT and STAT5 pathways. Circulating blasts are dependent on FLT3 signaling for activation of the MEK/ERK pathways. Stromal cytokines may activate the MEK/ERK pathway in stromal leukemia blasts independent of FLT3-ITD signaling, such as through CXCL12/CXCR4 interactions, conferring resistance to the clinically available FLT3 inhibitors. (B) Concomitant inhibition of CXCR4 (plerixafor), Pi3K (Pi3K inhibitors: BKM-120, IPI-145, BYL-719), MEK/ERK (PD0325901, trametinib, MEK-162, E6201), AKT/mTOR (mTOR inhibitors: CCI-779, everolimus), NF-κB inhibitors (early clinical trials), PiM-kinase inhibitors (early clinical trials), and FLT3 produces a synergistic effect in sorafenib-resistant cell lines.