Table 4.
In vitro sensitivity of unmutated BCR-ABL1 and of some more frequent BCR-ABL1 kinase domain mutants to imatinib, nilotinib, dasatinib, bosutinib, and ponatinib
| BCR-ABL1 | Imatinib IC50, range (nM) | Nilotinib IC50, range (nM) | Dasatinib IC50, range (nM) | Bosutinib IC50 (nM) | Ponatinib IC50 (nM) |
|---|---|---|---|---|---|
| Unmutated | 260-678 | <10-25 | 0.8-1.8 | 41.6 | 0.5 |
| M244V* | 1600-3100 | 38-39 | 1.3 | 147.4 | 2.2 |
| L248V | 1866-10 000 | 49.5-919 | 9.4 | NA | NA |
| G250E* | 1350 to >20 000 | 48-219 | 1.8-8.1 | 179.2 | 4.1 |
| Q252H | 734-3120 | 16-70 | 3.4-5.6 | 33.7 | 2.2 |
| Y253F | >6400-8953 | 182-725 | 6.3-11 | 40 | 2.8 |
| Y253H* | >6400-17 700 | 450-1300 | 1.3-10 | NA | 6.2 |
| E255K* | 3174-12 100 | 118-566 | 5.6-13 | 394 | 14 |
| E255V | 6111-8953 | 430-725 | 6.3-11 | 230.1 | 36 |
| D276G | 1147 | 35.3 | 2.6 | 25 | NA |
| E279K | 1872 | 36.5-75 | 3 | 39.7 | NA |
| V299L | 540-814 | 23.7 | 15.8-18 | 1086 | NA |
| F311L | 480-1300 | 23 | 1.3 | NA | NA |
| T315I* | >6400 to >20 000 | 697 to >10 000 | 137 to >1000 | 1890 | 11 |
| T315A | 125 | N.A. | 760 | NA | 1.6 |
| F317L* | 810-7500 | 39.2-91 | 7.4-18 | 100.7 | 1.1 |
| F317V | 500 | 350 | NA | NA | 10 |
| M351T* | 880-4900 | 7.8-38 | 1.1-1.6 | 29.1 | 1.5 |
| F359V* | 1400-1825 | 91-175 | 2.2-2.7 | 38.6 | 10 |
| V379I | 1000-1,630 | 51 | 0.8 | NA | NA |
| L384M* | 674-2800 | 39-41.2 | 4 | 19.5 | NA |
| L387M | 1000-1100 | 49 | 2 | NA | NA |
| H396R* | 1750-5400 | 41-55 | 1.3-3 | 33.7 | NA |
| H396P | 850-4300 | 41-43 | 0.6-2 | 18.1 | 1.1 |
| F486S | 2728-9100 | 32.8-87 | 5.6 | 96.1 | NA |
| Plasma drug concentration | |||||
| Cmin | 2062 ± 1334 | 1923 ± 1233 | 5.5 ± 1.4 | 268 (30-1533) | 64.3 ± 29.2 |
| Cmax | 4402 ± 1272 | 2329 ± 772 | 133 ± 73.9 | 392 (80-1858) | 145.4 ± 72.6 |
The half maximal inhibitory concentration (IC50) shown here is universally regarded as a measure of the degree of sensitivity of a BCR-ABL1 mutant to a given TKI and is experimentally determined by quantifying the TKI concentration required to reduce by 50% viability of a Ba/F3 mouse lymphoblastoid cell line engineered to express that mutant form of BCR-ABL1. The table lists all of the BCR-ABL1 mutants for which the IC50 values of at least 2 TKIs are available. For imatinib, dasatinib, and nilotinib, ranges of IC50 values were provided when differences in IC50 values reported by different studies were observed (reviewed in Baccarani et al5). For bosutinib and ponatinib, IC50 values come from a single study each.68,71 Plasma drug concentration is also given in nM. Values of plasma drug concentration are mean ± standard deviation for imatinib (400 mg once daily), nilotinib (300 mg twice daily), dasatinib (100 mg once daily), and ponatinib (45 mg once daily), and median (range) for bosutinib (500 mg once daily).34,50,72-75
NA, not available.