Table 2.
Prioritized KIT Resistance Mutations
| Compound | No. of Pred Mut (No. of All Mut)a | Rank 1 Resistance Hotspot (No. of Mut)b | Confirmed Clinical Resistance Mutants (Rank relP)c | Rank 2 Resistance Hotspot (No. of Mut)b | Confirmed Clinical Resistance Mutants (Rank relP) | Rank 3 Resistance Hotspot (No. of Mut)b | Confirmed Clinical Resistance Mutants (Rank relP) |
|---|---|---|---|---|---|---|---|
| Imatinib | 68 (648) | T670 (8) |
T670I (1) (Antonescu et al., 2005, Tamborini et al., 2004) T670E (6) (Wardelmann et al., 2005) |
C809 (7) | NRd | V668 (6) | NR |
| Sunitinib | 33 (468) | A814 (6) | NR | G596 (5) | NR | A621 (4) V654 (4) |
NR |
| Ponatinib | 64 (630) | C809 (8) | NR | T670 (5) C788 (5) |
(T670I)e | NAf | – |
See also Table S3.
Number of mutants that have been predicted to confer resistance (no. of pred mut) from the initial pool of possible mutants within 5 Å of the ligand (no. of all mut).
Resistance hotspots are identified and ranked according to the number of viable mutants (no. of mut) predicted for a residue.
RelP was calculated for all resistance hotspot mutations. Clinically observed resistance mutations and their rank according to relP (rank relP) are highlighted for each resistance hotspot.
NR, not reported––none of the predicted mutations has yet been reported to confer resistance to the drug.
T670I was predicted to confer resistance to ponatinib; however, T670I is reported to be sensitive to ponatinib (Garner et al., 2014).
NA, not applicable, tied resistance hotspot at rank 2. The gatekeeper mutation is underlined.