Table 2.

Known therapeutic strategies to overcome resistance to targeted therapies. Mainly evidence is restricted to findings in vitro or mice

Mutation	Resistant drug	Theoretical treatment option	Clinical experience	References
Flt3 on-target mutations	FLT3 inhibitor	Sequential use of FLT3i F691L confers resistance to all known FLT3i	Exposure to another FLT3i after midostaurin induced CR in 29%, FLT3i after quizartinib induced CR in 20%; quizartinib after sorafenib induced CR in 25%, no experience with second FLT3i after gilteritinib	[57]
Upregulation of soluble downstream factors	FLT3 inhibitor	FGF2 inhibitor CXCR4 inhibitor	In vitro evidence only for FGF2 inhibition CXCR4 inhibitor AMD3465 in combination with cytarabine eliminated leukemic blasts in mice	[44, 46]
Upregulation of downstream-pathways	FLT3 inhibitor	AXL inhibitors/ gilteritinib STAT5 inhibitors PIM inhibitor JAK inhibitor	The AXL inhibitor TP-0903 showed prolonged survival in combination with FLT3 inhibition in mice In vitro evidence only for PIM and JAK inhibitors	[31, 47, 50–52]
Increased intracellular pH	FLT3 inhibitor	NHE1 inhibitor	In vitro evidence and engraftment experiments in mice only	[53]
Upregulation of FLT3-ligand	Flt3 inhibitor	Flt3 inhibitor with higher plasma levels, higher affinity to Flt3	Not known	[42]
Binding site polymorphism	GO	Not known
Increased drug degradation	GO	Not known
Upregulation of PI3K-pathways	GO	AKT-inhibitor	In vitro evidence only	[91]
Mutation at binding site	IDH1/2 inhibitors	Not known
Isotype switch	IDH1/2 inhibitors	Ivosidenib after enasidenib; Enasidenib after ivosidenib; Bivalent inhibitors e.g. Ly3410738	Clinical studies ongoing	[74, 75]
Upregulation of downstream pathways	IDH1/2 inhibitors	RAS inhibitor	Not known	[69]
Alternative energy sources	IDH1/2 inhibitors	OXPHOS inhibitor	Effect of combined IDH and OXPHOS inhibition in mice	[76]
Increased expression of MCL-1 or BCL-XL	Venetoclax	MCL-1 or BCL-XL inhibitors	In vitro evidence only	[101]
Utilization of alternative energy sources such as fatty acid metabolism/NADP +	Venetoclax	Inhibition of FAO	In vitro evidence only	[105]