Table 5.
Prioritized ALK 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) |
|---|---|---|---|---|---|---|---|
| Crizotinib | 65 (378) | G1269 (13) | G1269A (4) (Doebele et al., 2012, Gainor et al., 2016) | G1202 (12) | G1202R (2) (Gainor et al., 2016) | I1122 (7) G1201 (7) D1203 (7) |
NRd |
| Ceritinib | 71 (414) | G1202 (12) | G1202R (2) (Gainor et al., 2016) | G1269 (10) D1203 (10) |
D1203N (1) (Gainor et al., 2016) | NAe | – |
| Entrectinib | 88 (451) | G1123 (15) | NR | G1269 (13) | NR | G1202 (12) | NR |
| Lorlatinib | 58 (360) | G1269 (13) | NR | G1123 (8) D1203 (8) |
NR | NA | – |
See also Table S6.
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 each 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 were reported to confer resistance against the drug. In the case of entrectinib and lorlatinib clinical resistance data are not yet available.
NA, not applicable, tied resistance hotspot at rank 1 or 2.