Table 1.

Inhibition of cell growth by GSK2118436, GSK1120212, GSK2126458, and their combination in A375 clones with acquired resistance to GSK2118436

Single agent IC50 (μmol/L)GSK2118436 +GSK1120212GSK2118436 +GSK2126458GSK1120212 +GSK2126458
CloneNRASMEK1GSK2118436GSK1120212GSK2126458IC50aEOHSAbIC50cEOHSAIC50dEOHSACIe
A375fWTWT0.028 ± 0.0160.005 ± 0.0030.050 ± 0.0170.007 ± 0.00519 ± 10.025 ± 0.01813 ± 30.003 ± 0.00114 ± 30.45 ± 0.13
12R5-3A146TWT>100.107 ± 0.0460.130 ± 0.1060.252 ± 0.07028 ± 50.505 ± 0.08512 ± 20.027 ± 0.01031 ± 60.50 ± 0.08
12R8-1A146TWT>100.062 ± 0.0310.128 ±0.0370.266 ± 0.13629 ± 80.984 ± 0.37214 ± 60.022 ± 0.00424 ± 120.65 ± 0.15
12R8-3A146TWT>100.082 ± 0.0300.167 ± 0.0410.178 ± 0.18227 ± 10.612 ± 0.00823 ± 40.045 ± 0.02125 ± 210.75 ± 0.31
16R6-3A146TP387S>100.147 ± 0.0640.131 ± 0.0750.280 ± 0.12336 ± 90.731 ± 0.2043 ± 30.019 ± 0.00531 ± 60.33 ± 0.09
16R5-5Q61KP387S>100.121 ± 0.0420.142 ± 0.0930.268 ± 0.07236 ± 30.833 ± 0.37223 ± 70.021 ± 0.00233 ± 60.45 ± 0.08
16R6-2Q61KP387S>100.123 ± 0.0650.065 ± 0.0470.242 ± 0.05728 ± 80.304 ± 0.1038 ± 10.011 ± 0.00333 ± 30.28 ± 0.11
16R6-4Q61K, A146TP387S>10>0.90.161 ± 0.1400.380 ± 0.169>500.495 ± 0.12321 ± 130.047 ± 0.03230 ± 30.31 ± 0.08
12R5-1WTK59del>10>10.177 ± 0.0990.392 ± 0.14919 ± 10.736 ± 0.16930 ± 50.037 ± 0.00725 ± 21N/Ag
12R5-5WTK59del>10>0.90.162 ± 0.0830.383 ± 0.10146 ± 120.640 ± 0.03335 ± 130.024 ± 0.00733 ± 60.24 ± 0.06
  • aIC50 for GSK2118436 dosed in a 10:1 molar to molar combination with GSK1120212 expressed in μmol/L.

  • bEOSHA, excess over single agent expressed as percentage points.

  • cIC50 for GSK2118436 dosed in a 10:1 molar to molar combination with GSK2126458 expressed in μmol/L.

  • dIC50 for GSK1120212 dosed in a 1:1 molar to molar combination with GSK2126458 expressed in μmol/L.

  • eCI, combination index for GSK1120212 and GSK2126458.

  • fCombination index for GSK2118436 + GSK1120212 = 0.49 ± 0.28, GSK2118436 + GSK2126458 = 0.43 ± 0.20.

  • gN/A, not applicable.