Table 4. MEK and PI3K/AKT pathway inhibitors display synergy in approximately half of the tested primary T-ALL samples.
| Mutations AND ID T-ALL patients | Inhibitor 1 | Inhibitor 2 | Inhibitor 1+2 | Synergy | |||
|---|---|---|---|---|---|---|---|
| MEK1/2 inhibitor | IC50 (nM) (% efficacy) | PI3K, mTOR, or AKT inhibitor | IC50 (nM) (% efficacy) | CI at ED50 (mean ±s.d.) | CI at ED75 (mean ±s.d.) | ||
| TLX3tr, mutations in IL7Ra, NRAS, NOTCH1 (HD domain), WT1, BCL11B, CDH9, STIL | |||||||
| 6 | AZD6244 | 79 (73%) | GDC-0941 | 346 (63%) | 0.39±0.02 | N/A | + |
| trametinib | 2 (80%) | GDC-0980 | 210 (64%) | 0.79±0.18 | 0.36±0.17 | + | |
| HOXA (Inv(7)), mutations in IL7Ra, NOTCH1 (PEST domain), WT1, ZNF717 | |||||||
| 7 | AZD6244 | 214 (51%) | GDC-0941 | 848 (87%) | 0.29±0.15 | 0.11±0.05 | + + |
| trametinib | 132 (79%) | GDC-0980 | 156 (86%) | 0.76±0.06 | 0.47±017 | + | |
| TLX3tr, TCRyd+, mutation in WT1, no mutations in NOTCH1, IL7Ra, JAK1, JAK3, N/K-RAS | |||||||
| 3976 | AZD6244 | 143 (56%) | GDC-0941 | 540 (62%) | 0.33±0.01 | 0.39 | + |
| AZD6244 | 143 (56%) | MK-2206 | 2594 (73%) | 0.49±0.23 | 0.61±0.18 | + | |
| 3543 | AZD6244 | ND (<20%) | GDC-0941 | 925 (84%) | 0.79±0.07 | 0.81±0.09 | + |
| trametinib | ND (<20%) | GDC-0980 | 322 (93%) | 0.82±0.09 | 0.79±0.07 | + | |
| 9175 | AZD6244 | 101 (44%) | GDC-0941 | 351 (85%) | 0.65±0.02 | 0.39±0.07 | + |
| AZD6244 | 101 (44%) | MK-2206 | 105 (68%) | 0.49±0.08 | N/A | + | |
| 9791 | AZD6244 | 95 (31%) | GDC-0941 | 195 (87%) | 0.52±0.23 | 0.28±0.09 | + |
| AZD6244 | 64 (34%) | MK-2206 | 72 (60%) | 0.54±0.10 | N/A | + | |
| trametinib | 53 (64%) | GDC-0980 | 54 (78%) | 0.34±0.08 | 0.07±0.04 | + + | |
| HOXA, mutations in IL7Ra, NOTCH1 (JM domain), FREM2, RUNX1 | |||||||
| 11 | AZD6244 | 32 (22%) | GDC-0941 | 164 (<20%) | N/A | N/A | N/A |
| trametinib | 175 (45%) | GDC-0980 | 404 (52%) | N/A | N/A | N/A | |
| LMO3-TCRBtr, mutations in PTEN, BCL11B, no mutations in NOTCH1, IL7Ra, JAK1, JAK3, N/K-RAS | |||||||
| 53 | AZD6244 | ND (<20%) | GDC-0941 | 473 (60%) | N/A | N/A | N/A |
| AZD6244 | ND (<20%) | MK-2206 | 125 (49%) | N/A | N/A | N/A | |
| TCRyd+, no mutations in NOTCH1, IL7Ra, JAK1, JAK3, N/K-RAS | |||||||
| 3821 | AZD6244 | ND (<20%) | GDC-0941 | 2005 (20%) | N/A | N/A | N/A |
| AZD6244 | ND (<20%) | MK-2206 | ND (33%) | N/A | N/A | N/A | |
| 7267 | AZD6244 | ND (<20%) | GDC-0941 | 278 (75%) | 0.87 | N/A | − |
| AZD6244 | ND (<20%) | MK-2206 | 72 (51%) | 1.17 | N/A | − | |
| 10880 | AZD6244 | ND (<20%) | GDC-0941 | 537 (56%) | 1.04±0.08 | N/A | − |
| trametinib | ND (66%) | GDC-0980 | 226 (65%) | 1.09±0.32 | 0.29±0.08 | −/+ | |
Note that patients # 6, 7, 11 and 46 correspond to those in Table 1. IC50 of each inhibitor in nM, with % efficacy indicated ND (<20%): IC50 could not be determined and the inhibitor had low maximum efficacy (<20%). CI: Mean Combination Index of the 1:1, 1:4 and 4:1 combinations at the 50% and 75% effective doses (ED50 and ED75) −: CI >1.0 (no synergy); +: CI <1.0 (synergy); ++: CI <0.3 (strong synergy); N/A, not applicable.