Mechanisms of resistance to targeted agents
| Disease . | Targeted therapy . | Primary target . | Mechanisms of resistance . | |
|---|---|---|---|---|
| Mutational . | Nonmutational . | |||
| FLT3-mutated AML | FLT3 inhibitors | FLT3 receptor kinase domain | Mutations that disrupt binding: | A. Upregulation of prosurvival pathways: MEK/ERK, Pi3K/AKT, STAT5/PIM |
| FLT3 activation loop residues (D835V/Y/F/H, D839G, Y842C/H) | ||||
| FLT3 gatekeeper residues (F691L/I) | ||||
| B. Upregulation of FLT3 receptor or FLT3 ligand | ||||
| C. Microenvironment/stroma-mediated resistance (CXCL12/CXCR4 signaling) | ||||
| D. Activation of antiapoptotic proteins (BCL2, MCL1) | ||||
| CLL | BTK inhibitors | BTK active site | A. Mutations that disrupt binding: BTK point mutations (C481S) | A. Upregulation of prosurvival pathways including Pi3K/AKT |
| B. Mutations producing BTK independent BCR pathway activation: PLCG2 mutations (R665W, L845F, S707Y) | B. Activation of antiapoptotic proteins (BCL-2) | |||
| CML | Tyrosine kinase inhibitors | BCR-ABL kinase domain | Mutations that disrupt binding: | A. Genomic amplification of BCR-ABL |
| Activation loop residues (this includes P-loop, SH3 and SH2 contact, and A-loop mutations)* | B. Clonal cytogenetic changes | |||
| Gatekeeper residues (T315I/A, F317L/V/I/C) | C. P-glycoprotein mediated drug efflux | |||
| D. Alternative pathway signal activation (Src family kinases) | ||||
| E. Loss of functional P53 | ||||
| APL | Arsenic trioxide | PML protein | Mutations that disrupt binding: | |
| PML locus (A216V/T, S214L, L217F, S220G) | ||||
| RAR locus (G197E, R2831, M284V, D288E) | ||||
| Chronic eosinophilic leukemia | Imatinib | PDGFRA-FLIP1L1 tyrosine kinase | Mutations that disrupt binding: ATP binding residues (T674I, D842V) | |
| Disease . | Targeted therapy . | Primary target . | Mechanisms of resistance . | |
|---|---|---|---|---|
| Mutational . | Nonmutational . | |||
| FLT3-mutated AML | FLT3 inhibitors | FLT3 receptor kinase domain | Mutations that disrupt binding: | A. Upregulation of prosurvival pathways: MEK/ERK, Pi3K/AKT, STAT5/PIM |
| FLT3 activation loop residues (D835V/Y/F/H, D839G, Y842C/H) | ||||
| FLT3 gatekeeper residues (F691L/I) | ||||
| B. Upregulation of FLT3 receptor or FLT3 ligand | ||||
| C. Microenvironment/stroma-mediated resistance (CXCL12/CXCR4 signaling) | ||||
| D. Activation of antiapoptotic proteins (BCL2, MCL1) | ||||
| CLL | BTK inhibitors | BTK active site | A. Mutations that disrupt binding: BTK point mutations (C481S) | A. Upregulation of prosurvival pathways including Pi3K/AKT |
| B. Mutations producing BTK independent BCR pathway activation: PLCG2 mutations (R665W, L845F, S707Y) | B. Activation of antiapoptotic proteins (BCL-2) | |||
| CML | Tyrosine kinase inhibitors | BCR-ABL kinase domain | Mutations that disrupt binding: | A. Genomic amplification of BCR-ABL |
| Activation loop residues (this includes P-loop, SH3 and SH2 contact, and A-loop mutations)* | B. Clonal cytogenetic changes | |||
| Gatekeeper residues (T315I/A, F317L/V/I/C) | C. P-glycoprotein mediated drug efflux | |||
| D. Alternative pathway signal activation (Src family kinases) | ||||
| E. Loss of functional P53 | ||||
| APL | Arsenic trioxide | PML protein | Mutations that disrupt binding: | |
| PML locus (A216V/T, S214L, L217F, S220G) | ||||
| RAR locus (G197E, R2831, M284V, D288E) | ||||
| Chronic eosinophilic leukemia | Imatinib | PDGFRA-FLIP1L1 tyrosine kinase | Mutations that disrupt binding: ATP binding residues (T674I, D842V) | |
Supplemental Figure 1 provides detailed information regarding activation loop mutations in CML.