Concomitant Targeting of FLT3 and BTK with CG'806 Overcomes FLT3-Inhibitor Resistance through Inhibition of Autophagy

Fms-like tyrosine kinase 3 (FLT3)-targeted therapy represents an important paradigm in the management of patients with highly aggressive FLT3 mutated acute myeloid leukemia (AML). However, clinical efficacy is usually transient and followed by emergence of resistance to FLT3-inhibitors (Borthakur et al., 2011; Cortes et al., 2013; Zhang et al., 2008). Such resistance often results from acquired mutations of TKD, which are frequently identified in D835, Y842 and F691 residues (Smith et al., 2015; Smith et al., 2012; Zhang et al., 2014). It was reported that the FLT3-ITD-targeting drug sorafenib can induce autophagy in human myeloid dendritic cells (Lin et al., 2013). Induction of autophagy has also been reported to play a crucial role in resistance to BCR-ABL targeted imatinib therapy in CML (Hekmatshoar et al., 2018). Additionally, inhibition of autophagy can re-sensitize cancer cells to apoptosis induction (Fitzwalter et al., 2018; Piya et al., 2017), suggesting that inhibition of autophagy may represent a novel therapeutic strategy for overcoming resistance to FLT3-targeted therapy.In the present study, we assessed autophagy levels in leukemia cell lines bearing different FLT3 mutations and in AML patient samples obtained from sorafenib-resistant patients. All tested resistant cell lines bearing TKD or ITD+TKD mutations showed increased basal autophagy levels. Resistant AML patient samples also demonstrated greater autophagy compared to matched pre-treatment samples in FLT3...
Source: Blood - Category: Hematology Authors: Tags: 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Poster II Source Type: research