Table 1. Effects of IBET-726 and trametinib alone and in combination across neuroblastoma cell line models annotated with clinically relevant mutations.
Genomic analysis was performed utilizing a focused gene panel (Foundation Medicine platform). Cell lines are ranked according to synergy scores (most to least sensitive). Synergy values were determined by Chalice analysis of cell survival data obtained from CellTiter-Glo assays using a matrix treatment schedule from 1/4x-4x IC50 (+++++ very strong synergy; ++++ strong synergy; +++ synergy; ++ moderate synergy; + slight synergy; +/− additive, - antagonistic).
| Cell Line | MYCN Status | MYC Amplification | MYC Expression (FPKM) | RAS-MAPK Pathway Mutations | ALK Mutations | TP53 Mutations | MDM2 Amplification | NF1 Deletion | IC50 GSK726 (nM) | IC50 Trametinib (nM) | Combination Index | Synergy |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| NB1691 | MYCN amplified | Non-amp | 0.12 | Amplified | 1142 | 508 | 0.03 | +++++ | ||||
| SK-N-FI | Non-amp | 1.75 | M246R | Deletion (homozygous) |
1023 | 40 | 0.2 | ++++ | ||||
| NLF | MYCN amplified | Non-amp | 0.13 | V203M | 875 | 248 | 0.03 | +++++ | ||||
| NB-SD | MYCN amplified | Non-amp | 0.01 | FGFR1 P770S | F1174L | C176F | 820 | 66 | 0.35 | +++ | ||
| SMS-SAN | MYCN amplified | Non-amp | 0.03 | F1174L | 797 | 1275 | 0.28 | ++++ | ||||
| SK-N-BE(2)-C | MYCN amplified | Non-amp | 0.06 | NF1 N664fs | C135F | Deletion (hemizygous) | 706 | 64 | 0.18 | ++++ | ||
| NGP | MYCN amplified | Non-amp | 0.12 | A159D C141W |
541 | 91 | 0.92 | ± | ||||
| NB-1643 | MYCN amplified | Non-amp | 0.02 | R1275Q | 515 | 341 | 0.35 | +++ | ||||
| NB69 | Non-amp | 165.14 | Deletion (hemizygous) | 279 | 3920 | 0.59 | +++ | |||||
| NB-Ebc1 | Non-amp | 0.12 | KRAS G12D | 271 | 15 | 0.44 | +++ | |||||
| LA-N-5 | MYCN amplified | Non-amp | 0.07 | R1275Q | 186 | 426 | 0.49 | +++ | ||||
| SK-N-AS | Non-amp | 10.24 | NRAS Q61K | 166 | 8 | 0.69 | +++ | |||||
| SK-N-BE(2) | MYCN amplified | Non-amp | 0.24 | NF1 N664fs | C135F | 157 | 61 | 0.03 | +++++ | |||
| IMR-05 | MYCN amplified | Non-amp | 0.00 | 109 | 262 | 0.29 | ++++ | |||||
| SK-N-DZ | MYCN amplified | Non-amp | 0.02 | R110L | 91 | 13,470 | 0.53 | +++ | ||||
| Kelly | MYCN amplified | Non-amp | 0.02 | F1174L | P177T | 86 | 174 | 0.2 | ++++ | |||
| NBL-S | Non-amp | 0.19 | 50 | 19 | 0.22 | ++++ | ||||||
| SY-5Y | Non-amp | 15.63 | PTPN11 T507K | F1174L | 30 | 43 | 0.35 | +++ | ||||
| CHP-212 | MYCN amplified | Non-amp | 0.05 | NRAS Q61K | 30 | 31 | 0.15 | ++++ | ||||
| SK-N-SH | Non-amp | 25.72 | F1174L | 28 | 72 | 0.68 | +++ | |||||
| CHP-134 | MYCN amplified | Non-amp | 0.18 | 25 | 312,400 | 0.83 | ++ |
| CI Interval | Symbol | Observed synergy |
|---|---|---|
| <0.1 | +++++ | Very strong |
| 0.1 – 0.3 | ++++ | Strong |
| 0.3 – 0.7 | +++ | Synergy |
| 0.7 – 0.85 | ++ | Moderate synergism |
| 0.85 – 0.9 | + | Slight synergism |
| 0.9 – 1.1 | ± | Additive |
| >0.1 | - | Antagonistic |