Resistance to FLT3 inhibitors in acute myeloid leukemia: Molecular mechanisms and resensitizing strategies

Table 1 Summary of main studies on primary and acquired resistance to FMS-like tyrosine kinase 3 inhibitors

	Ref.	Disease model (method and material)	Mechanisms of resistance
Primary resistance	Grundler et al[32], 2003	Site-directed mutagenesis, murine Ba/F3	TKD mutation, deletion or insertion
	Clark et al[33], 2004	Site-directed mutagenesis, murine Ba/F3	TKD mutation
	Bagrintseva et al[37], 2005	Site-directed mutagenesis, murine Ba/F3	ITD-TKD mutation, Bcl-xL overexpression
Acquired resistance	Weisberg et al[45], 2002	Coculture with PKC412, murine Ba/F3-FLT3-ITD	FLT3 protein overexpression
	Bagrintseva et al[46], 2004	Coculture with SU5614, murine Ba/F3-FLT3-ITD	ITD-TKD mutation, FLT3 protein overexpression
	Cools et al[47], 2004	Random PCR mutagenesis, murine Ba/F3-FLT3-ITD	ITD-TKD mutation
	Heidel et al[48], 2006	PKC412 clinical trial, relapsed AML with ITD	ITD-TKD (N676K) mutation
	Piloto et al[49], 2007	Coculture with CEP-5214 and CEP-701, human MOLM-14, Hb1119 and SEM-K2	RTK amplification, N-Ras mutation
	Zhou et al[50], 2009	Coculture with ABT-869, human MV4-11	Overactivation of STAT, overexpression of Survivin

FLT3: FMS-like tyrosine kinase 3; ITD: Internal tandem duplication; TKD: Tyrosine kinase domain; RTK: Receptor tyrosine kinase; STAT: Signal transducer and activator of transcription.