Frequency and in vitro sensitivity of clinically isolated BCR-ABL KD mutants to imatinib in various assays
. | . | . | . | IC50, μM . | . | . | ||
|---|---|---|---|---|---|---|---|---|
| Wild-type ABL numbering according to ABL exon Ia/Ib . | Exchange . | Patients, total = 177 . | % . | BCR-ABL phosphorylation in cells . | ABL autophosphorylation (in vitro kinase assay) . | Cell proliferation . | ||
| M244/M263 | V | 3 | 1.69 | NR* | 0.03, 0.64, 1 | 1, 1.6 | ||
| L248/L267† | V | 1 | 0.56 | NR* | NR | NR | ||
| G250/G269 | E | 6 | 3.39 | 7.4 to > 10 | 1.6 | 4.5 to > 20 | ||
| G250/G269 | A | 1 | 0.56 | NR | NR | NR | ||
| Q252/Q271 | H | 8 | 4.52 | 2.9, 10.4 | NR | 2.8 to 9.3 | ||
| Q252/Q271 | R | 1 | 0.56 | 10.4 | NR | NR | ||
| Y253/Y272 | F | 6 | 3.39 | 5.9, 21.4 | 72 | 3 to 8.9 | ||
| Y253/Y272 | H | 12 | 6.78 | 21.4 | 150 | 17.7, > 33 | ||
| E255/E274 | K | 34 | 19.21 | 27.9 | > 200 | 15 to 33 | ||
| E255/E274 | V | 4 | 2.26 | 7.3 | 3.5, > 200 | 7.7, > 33 | ||
| D276‡/D295 | G | 1 | 0.56 | NR | NR | NR | ||
| F311/F330 | L | 1 | 0.56 | NR* | 0.031, 1 | 0.7 to 2.1 | ||
| T315/T334 | I | 37 | 20.9 | > 10 | > 10 | 5.2 to > 10 | ||
| T315/T334 | N | 1 | 0.56 | NR | NR | NR | ||
| F317/F336 | L | 7 | 3.95 | 0.8 to 11.8 | 0.25, 0.38, 8.3 | 1.3 to 13 | ||
| M343/M362 | T | 1 | 0.56 | NR | NR | NR | ||
| M351/M370 | T | 27 | 15.25 | 0.6 to 3.9 | 0.26, < 1 | 0.9 to 7.3 | ||
| E355/E374 | G | 5 | 2.82 | 2.8, 10 | 0.02, 0.8 | 2.3, 4 | ||
| F359/F378 | A | 1 | 0.56 | NR | NR | NR | ||
| F359/F378 | V | 7 | 3.95 | NR | 0.05, 1.8 | 1.4, 2.8 | ||
| V379/V398 | I | 1 | 0.56 | NR | 0.03, 1.1 | 1, 2 | ||
| F382/F401 | L | 1 | 0.56 | NR | NR | NR | ||
| L387/L406 | M | 1 | 0.56 | NR | 0.06, 2.1 | 1.1, 2.2 | ||
| H396/H415 | P | 1 | 0.56 | NR | 0.34, 0.87 | 1.4 to 4.3 | ||
| H396/H415 | R | 6 | 3.39 | NR | 0.22, 7.3 | 5.4, 11 | ||
| S417/S436 | Y | 1 | 0.56 | NR | NR | 1.8 | ||
| E459/E478 | K | 1 | 0.56 | NR | NR | NR | ||
| F486/F505 | S | 1 | 0.56 | 1.1 | 0.67 | 1.4, 9.1 | ||
. | . | . | . | IC50, μM . | . | . | ||
|---|---|---|---|---|---|---|---|---|
| Wild-type ABL numbering according to ABL exon Ia/Ib . | Exchange . | Patients, total = 177 . | % . | BCR-ABL phosphorylation in cells . | ABL autophosphorylation (in vitro kinase assay) . | Cell proliferation . | ||
| M244/M263 | V | 3 | 1.69 | NR* | 0.03, 0.64, 1 | 1, 1.6 | ||
| L248/L267† | V | 1 | 0.56 | NR* | NR | NR | ||
| G250/G269 | E | 6 | 3.39 | 7.4 to > 10 | 1.6 | 4.5 to > 20 | ||
| G250/G269 | A | 1 | 0.56 | NR | NR | NR | ||
| Q252/Q271 | H | 8 | 4.52 | 2.9, 10.4 | NR | 2.8 to 9.3 | ||
| Q252/Q271 | R | 1 | 0.56 | 10.4 | NR | NR | ||
| Y253/Y272 | F | 6 | 3.39 | 5.9, 21.4 | 72 | 3 to 8.9 | ||
| Y253/Y272 | H | 12 | 6.78 | 21.4 | 150 | 17.7, > 33 | ||
| E255/E274 | K | 34 | 19.21 | 27.9 | > 200 | 15 to 33 | ||
| E255/E274 | V | 4 | 2.26 | 7.3 | 3.5, > 200 | 7.7, > 33 | ||
| D276‡/D295 | G | 1 | 0.56 | NR | NR | NR | ||
| F311/F330 | L | 1 | 0.56 | NR* | 0.031, 1 | 0.7 to 2.1 | ||
| T315/T334 | I | 37 | 20.9 | > 10 | > 10 | 5.2 to > 10 | ||
| T315/T334 | N | 1 | 0.56 | NR | NR | NR | ||
| F317/F336 | L | 7 | 3.95 | 0.8 to 11.8 | 0.25, 0.38, 8.3 | 1.3 to 13 | ||
| M343/M362 | T | 1 | 0.56 | NR | NR | NR | ||
| M351/M370 | T | 27 | 15.25 | 0.6 to 3.9 | 0.26, < 1 | 0.9 to 7.3 | ||
| E355/E374 | G | 5 | 2.82 | 2.8, 10 | 0.02, 0.8 | 2.3, 4 | ||
| F359/F378 | A | 1 | 0.56 | NR | NR | NR | ||
| F359/F378 | V | 7 | 3.95 | NR | 0.05, 1.8 | 1.4, 2.8 | ||
| V379/V398 | I | 1 | 0.56 | NR | 0.03, 1.1 | 1, 2 | ||
| F382/F401 | L | 1 | 0.56 | NR | NR | NR | ||
| L387/L406 | M | 1 | 0.56 | NR | 0.06, 2.1 | 1.1, 2.2 | ||
| H396/H415 | P | 1 | 0.56 | NR | 0.34, 0.87 | 1.4 to 4.3 | ||
| H396/H415 | R | 6 | 3.39 | NR | 0.22, 7.3 | 5.4, 11 | ||
| S417/S436 | Y | 1 | 0.56 | NR | NR | 1.8 | ||
| E459/E478 | K | 1 | 0.56 | NR | NR | NR | ||
| F486/F505 | S | 1 | 0.56 | 1.1 | 0.67 | 1.4, 9.1 | ||
The values are given as fold changes over wild type. The data are compiled from several studies.83,84,89-98
NR indicates not reported.
Immunoblots were published but IC50 values were not given.94
L267R had greater than 33-fold increased resistance in proliferation assays.
D276V had greater than 2-fold increased resistance in proliferation assays.