Tyrosine kinase inhibitors: Multi-targeted or single-targeted?

Table 5 Resistance mechanism to tyrosine kinase inhibitors

	Mechanism	Target/drug/disease	Ref.
1	(Secondary) mutation of the tyrosine kinase	Bcr-Abl in CML, FLT3 in AML, EGFR in NSCLC, c-KIT in GIST	[12]
2	Gene amplification and subsequent overexpression of the protein kinase	Bcr-Abl in CML + c-KIT in GIST	[12]
3a	Activation of other signaling pathways	PDGFR mutation in c-KIT mutated GIST, MET overexpression in EGFR mutated NSCLC	[50]
3b	Overexpression of kinases downstream of the kinase	LYN in CML
4	Lower intracellular drug concentrations because of:
4a	Extracellular sequestration of the inhibitor by binding to α acid glycoprotein	PKC412, imatinib	[99]
4b	Decreased expression or activity of drug influx pumps	OCT1, imatinib	[52]
4c	Increased expression or activity of drug efflux pumps	BCRP, P-glycoprotein (imatinib)	[51,60]

NSCLC: Non small cell lung cancer; PDGFR: Platelet derived growth factor receptor; EGFR: Epidermal growth factor receptor; CML: Chronic myeloid leukemia; GIST: Gastrointestinal stromal tumors; AML: Acute myeloid leukaemia.