Effects of imatinib mesylate and nilotinib on known imatinib mesylate–resistant mutant forms of Bcr-Abl
Bcr-Abl form or construct . | Imatinib mesylate . | . | Nilotinib . | . | ||
|---|---|---|---|---|---|---|
| . | Autophosphorylation . | Proliferation . | Autophosphorylation . | Proliferation . | ||
| Wild-type p185 | 208 (2) | 430 ± 11 (9) | 49 (2) | 28 ± 7 (12) | ||
| M2371 | 399 (2) | 1545 (2) | 34 (2) | 35 (2) | ||
| L248V | 1011 (2) | 2081 (2) | 83 ± 7 (3) | 102 ± 13 (4) | ||
| G250A | 313 (2) | 1269 (2) | 46 (2) | 65 (2) | ||
| G250V | 489 (2) | 624 (2) | 54 (2) | 19 (2) | ||
| E255D | 754 (2) | 1082 (2) | 51 (2) | 24 (2) | ||
| E255R | 1877 (2) | 1567 (2) | 235 (2) | 57 (2) | ||
| E275K | 1038 (2) | 563 (2) | 125 (2) | 29 (2) | ||
| D276G | 1284 (2) | 2486 (2) | 107 (2) | 77 (2) | ||
| E281K | 584 (2) | 1601 (2) | 39 (2) | 49 (2) | ||
| E285N | 919 (2) | 1264 (2) | 188 (2) | 63 (2) | ||
| F311V | 1480 (2) | 3535 (2) | 84 ± 2 (3) | 155 ± 31 (4) | ||
| F317C | 1090 (2) | 694 (2) | 57 (2) | 19 (2) | ||
| F317V | 544 ± 47 (3) | 549 ± 173 (4) | 95 ± 28 (3) | 28 ± 4 (4) | ||
| D325N | 584 (2) | 887 (2) | 69 (2) | 25 (2) | ||
| S348L | 553 (2) | 1370 (2) | 54 (2) | 26 (2) | ||
| E355A | 676 (2) | 1434 (2) | 91 (2) | 38 (2) | ||
| E355G | 601 (2) | 1149 (2) | 67 ± 15 (3) | 47 ± 8 (4) | ||
| F359C | 1130 (2) | 2377 (2) | 201 (2) | 291 (2) | ||
| A380S | 2617 (2) | 3744 (2) | 125 (2) | 179 (2) | ||
| L387F | 530 (2) | 172 (2) | 172 (2) | 39 (2) | ||
| M388L | 517 (2) | 525 (2) | 68 (2) | 20 (2) | ||
Bcr-Abl form or construct . | Imatinib mesylate . | . | Nilotinib . | . | ||
|---|---|---|---|---|---|---|
| . | Autophosphorylation . | Proliferation . | Autophosphorylation . | Proliferation . | ||
| Wild-type p185 | 208 (2) | 430 ± 11 (9) | 49 (2) | 28 ± 7 (12) | ||
| M2371 | 399 (2) | 1545 (2) | 34 (2) | 35 (2) | ||
| L248V | 1011 (2) | 2081 (2) | 83 ± 7 (3) | 102 ± 13 (4) | ||
| G250A | 313 (2) | 1269 (2) | 46 (2) | 65 (2) | ||
| G250V | 489 (2) | 624 (2) | 54 (2) | 19 (2) | ||
| E255D | 754 (2) | 1082 (2) | 51 (2) | 24 (2) | ||
| E255R | 1877 (2) | 1567 (2) | 235 (2) | 57 (2) | ||
| E275K | 1038 (2) | 563 (2) | 125 (2) | 29 (2) | ||
| D276G | 1284 (2) | 2486 (2) | 107 (2) | 77 (2) | ||
| E281K | 584 (2) | 1601 (2) | 39 (2) | 49 (2) | ||
| E285N | 919 (2) | 1264 (2) | 188 (2) | 63 (2) | ||
| F311V | 1480 (2) | 3535 (2) | 84 ± 2 (3) | 155 ± 31 (4) | ||
| F317C | 1090 (2) | 694 (2) | 57 (2) | 19 (2) | ||
| F317V | 544 ± 47 (3) | 549 ± 173 (4) | 95 ± 28 (3) | 28 ± 4 (4) | ||
| D325N | 584 (2) | 887 (2) | 69 (2) | 25 (2) | ||
| S348L | 553 (2) | 1370 (2) | 54 (2) | 26 (2) | ||
| E355A | 676 (2) | 1434 (2) | 91 (2) | 38 (2) | ||
| E355G | 601 (2) | 1149 (2) | 67 ± 15 (3) | 47 ± 8 (4) | ||
| F359C | 1130 (2) | 2377 (2) | 201 (2) | 291 (2) | ||
| A380S | 2617 (2) | 3744 (2) | 125 (2) | 179 (2) | ||
| L387F | 530 (2) | 172 (2) | 172 (2) | 39 (2) | ||
| M388L | 517 (2) | 525 (2) | 68 (2) | 20 (2) | ||
Ba/F3 cells were engineered to express mutant forms of Bcr-Abl p185 which are known to mediate resistance to imatinib mesylate, in extension to frequent clinical isolates already studied.30,37 A cell-capture enzyme linked immunosorbent assay was used to evaluate drug effects on Bcr-Abl kinase activity, and an ATLite assay (Perkin Elmer) was used to evaluate effects on cell growth. Results are expressed as mean IC50 values (nM) ± SEM (number of replicates).