Table 1.
Pairs of drug hits and corresponding genes with significant association between cytotoxicity and copy number.
| Drug | Mechanism of action | Mean cytotoxicity (S.D.) | Gene (mean copy number, z-score) |
|---|---|---|---|
| Staurosporine | TGF-beta/Smad | 95.7 ( ± 5.5) | GNA13 (2.9, 0.73); ABL2 (2, -0.81); GNA11 (1.8, 0.86) |
| BGT226 (NVP-BGT226) | PI3K/Akt/mTOR | 83.6 ( ± 16) | GNA11 (1.8, 0.86); MAP2K2 (1.8, 0.86); MPL (1.8, 0.82); JAK1 (2, 0.72) |
| P276-00 | Cell Cycle | 79.7 ( ± 14.5) | GNA13 (2.9, 1.23); PPM1D (3.2, 1.05); ASXL2 (2.1, -0.73); DNMT3A (2.1, -0.77); CBL (1.7, -1.01) |
| PIK-75 | PI3K/Akt/mTOR | 78.9 ( ± 14.5) | GNA13 (2.9, 1.4); PPM1D (3.2, 1.16); BRAF (2.2, 0.74); EZH2 (2.2, 0.74); MET (2.2, 0.74); SMO (2.2, 0.74); EED (1.8, -0.89); CBL (1.7, -1.41) |
| Tivantinib (ARQ 197) | Protein T.K. | 76.7 ( ± 11.2) | GNA13 (2.9, 0.88); PPM1D (3.2, 0.75); DNMT3A (2.1, -0.72); CBL (1.7, -0.99) |
| Flavopiridol (Alvocidib) | Cell Cycle | 75.4 ( ± 16.4) | GNA13 (2.9, 1.14); PPM1D (3.2, 1.04); ASXL2 (2.1, -0.71); DNMT3A (2.1, -0.77); EED (1.8, -0.79); CBL (1.7, -1.25) |
| Flavopiridol HCl | Cell Cycle | 73.4 ( ± 16.7) | GNA13 (2.9, 1.14); PPM1D (3.2, 1.07); EED (1.8, -0.77); CBL (1.7, -1.24) |
| SNS-032 (BMS-387032) | Cell Cycle | 70.8 ( ± 18) | GNA13 (2.9, 1.05); PPM1D (3.2, 0.98); EED (1.8, -0.75); CBL (1.7, -1.17) |
| Dinaciclib (SCH727965) | Cell Cycle | 70.7 ( ± 16.9) | GNA13 (2.9, 1); PPM1D (3.2, 0.98); ASXL2 (2.1, -0.7); DNMT3A (2.1, -0.79); CBL (1.7, -1.12) |
| INK 128 (MLN0128) | PI3K/Akt/mTOR | 70.5 ( ± 7.6) | CBL (1.7, -0.96) |
| Torin 2 | PI3K/Akt/mTOR | 70.4 ( ± 7.8) | JAK1 (2, 0.78); CBL (1.7, -0.83) |
| AT7519 | Cell Cycle | 70 ( ± 22.5) | GNA13 (2.9, 1.01); JAK1 (2, 0.89); PPM1D (3.2, 0.83); CBL (1.7, -0.81) |
| PF-04691502 | PI3K/Akt/mTOR | 69 ( ± 7.2) | CBL (1.7, -0.72) |
| GSK2126458 (GSK458) | PI3K/Akt/mTOR | 67.8 ( ± 8) | NF1 (2.2, -0.7); SUZ12 (2.2, -0.7); CBL (1.7, -0.8) |
| AZD8055 | PI3K/Akt/mTOR | 67.7 ( ± 8.9) | JAK1 (2, 0.77) |
| WYE-125132 (WYE-132) | PI3K/Akt/mTOR | 65.6 ( ± 7.7) | H3F3A (2.2, 0.75); MDM4 (2.2, 0.75); CBL (1.7, -0.89) |
| VS-5584 (SB2343) | PI3K/Akt/mTOR | 65.2 ( ± 7.9) | JAK1 (2, 0.77); MPL (1.8, 0.72) |
| AZD3463 | Protein T.K. | 65.2 ( ± 17.4) | TCF3 (2, 0.88); JAK1 (2, 0.7) |
| GDC-0980 (RG7422) | PI3K/Akt/mTOR | 64.5 ( ± 8.1) | JAK1 (2, 0.8); MPL (1.8, 0.71); TCF3 (2, 0.69) |
| AT9283 | JAK/STAT | 64.3 ( ± 17.4) | DNMT3A (2.1, -0.7); CBL (1.7, -0.72); CALR (1.8, -0.72); CEBPA (1.9, -0.72); CIC (1.8, -0.72); CRLF1 (1.9, -0.72); JAK3 (1.9, -0.72) |
| AZD2014 | PI3K/Akt/mTOR | 63.7 ( ± 9.1) | JAK1 (2, 0.87); MPL (1.8, 0.77) |
| PP242 | PI3K/Akt/mTOR | 57.6 ( ± 10.3) | TCF3 (2, 0.76); MPL (1.8, 0.75); JAK1 (2, 0.73) |
| Rigosertib (ON-01910) | Cell Cycle | 57.2 ( ± 10.9) | JAK1 (2, 0.89); PHF6 (2.1, 0.71) |
| PF-477736 | Cell Cycle | 56.2 ( ± 19.2) | JAK1 (2, 1) |
| JNK Inhibitor IX | MAPK | 55.6 ( ± 11.4) | JAK1 (2, 0.85) |
| PF-3758309 | Cytoskeletal Signaling | 55.2 ( ± 18.7) | JAK1 (2, 0.85); CBL (1.7, -0.94) |
| Milciclib (PHA-848125) | Cell Cycle | 55.2 ( ± 9.1) | ASXL1 (2.1, -0.7) |
| HMN-214 | Cell Cycle | 51.9 ( ± 13) | JAK1 (2, 0.72) |
| TAK-901 | Cell Cycle | 51.6 ( ± 18.3) | JAK1 (2, 0.85) |
| KX2-391 | Angiogenesis | 51.2 ( ± 9.4) | JAK1 (2, 0.76); GNA13 (2.9, 0.71); ASXL2 (2.1, -0.74); DNMT3A (2.1, -0.75) |
| Pelitinib (EKB-569) | Protein T.K. | 51 ( ± 13.7) | RUNX1 (2, -0.73) |
| CHIR-124 | Cell Cycle | 50.7 ( ± 12.7) | FBXW7 (2, -0.73); FGFR3 (2, -0.73); KDR (2, -0.73); KIT (2, -0.73); PDGFRA (2, -0.73); CBL (1.7, -0.98) |
| OSI-027 | PI3K/Akt/mTOR | 50.5 ( ± 8.1) | CRLF2 (1.4, 0.89); DDX3X (1.4, 0.89); KDM6A (1.4, 0.89); MPL (1.8, 0.77); ABL1 (2, 0.71); NOTCH1 (2, 0.71) |
| TG101209 | JAK/STAT | 48.5 ( ± 16.8) | TCF3 (2, 0.89) |
| GDC-0349 | PI3K/Akt/mTOR | 48.4 ( ± 11.1) | JAK1 (2, 0.72); TCF3 (2, 0.7) |
| KU-0063794 | PI3K/Akt/mTOR | 47 ( ± 11.5) | GNA11 (1.8, 0.85); MAP2K2 (1.8, 0.85) |
| HS-173 | PI3K/Akt/mTOR | 46.2 ( ± 12.6) | PHF6 (2.1, 0.76); MYCN (27.9, 0.7) |
| IMD 0354 | NF-KB | 45.6 ( ± 8.5) | GNA11 (1.8, 0.85); MAP2K2 (1.8, 0.85); PHF6 (2.1, 0.76); MYCN (27.9, 0.7); PPM1D (3.2, 0.72); SMARCA4 (1.9, -0.73); GNA11 (1.8, -0.84); MAP2K2 (1.8, -0.84); APC (2.1, -0.89); CSF1R (2.1, -0.89); EBF1 (2.1, -0.89); FGFR4 (2.1, -0.89); IL7R (2.1, -0.89) |
| AP26113 | Protein T.K. | 42.9 ( ± 21.3) | H3F3A (2.2, 0.89); MDM4 (2.2, 0.89); TCF3 (2, 0.78); JAK1 (2, 0.74); ARID1B (1.9, -0.7); CCND3 (1.9, -0.7); DAXX (1.9, -0.7); ESR1 (1.9, -0.7); HIST1H3B (1.9, -0.7) |
| LDK378 | Protein T.K. | 42.1 ( ± 28.8) | H3F3A (2.2, 0.95); MDM4 (2.2, 0.95); TCF3 (2, 0.91); GNA11 (1.8, 0.79); MAP2K2 (1.8, 0.79); ARID1B (1.9, -0.82); CCND3 (1.9, -0.82); DAXX (1.9, -0.82); ESR1 (1.9, -0.82); HIST1H3B (1.9, -0.82) |
| TG101348 (SAR302503) | JAK/STAT | 36.3 ( ± 17.3) | TCF3 (2, 0.9); H3F3A (2.2, 0.71); MDM4 (2.2, 0.71); GNA11 (1.8, 0.7); MAP2K2 (1.8, 0.7) |
| BI 2536 | Cell Cycle | 35.2 ( ± 16.6) | H3F3A (2.2, 0.82); MDM4 (2.2, 0.82) |
| FIIN-2 | Protein T.K. | 35.2 ( ± 17) | JAK1 (2, 0.75) |
| AZ20 | PI3K/Akt/mTOR | 35.2 ( ± 11) | JAK1 (2, 0.88) |
| Pacritinib (SB1518) | JAK/STAT | 35.1 ( ± 19.1) | H3F3A (2.2, 0.88); MDM4 (2.2, 0.88); TCF3 (2, 0.78); CBL (1.7, -0.72) |
| R547 | Cell Cycle | 34.8 ( ± 13.7) | CBL (1.7, -0.87) |
| R406 (free base) | Angiogenesis | 34.6 ( ± 10.8) | AKT1 (2.2, -0.8); DICER1 (2.2, -0.8); ASXL1 (2.1, -0.83); PIK3CA (2.1, -0.9); RUNX1 (2, -1.05) |
| AZD7762 | Cell Cycle | 34.3 ( ± 15.3) | JAK1 (2, 0.89) |
| Volasertib (BI 6727) | Cell Cycle | 33.2 ( ± 10.1) | H3F3A (2.2, 0.79); MDM4 (2.2, 0.79); MPL (1.8, 0.7) |
T.K., tyrosine kinase.