The AU565 cell line was derived from the same patient that gave rise to the more famous SKBR3 cell line. As such, both lines are characterized by an ERBB2 (HER2) gene amplification and TP53 mutation. The cell line was derived from a pleural effusion metastasis of a patient diagnosed with breast adenocarcinoma. The STR profile along with other data and references pertinent to this cell line can be found here at Cellosaurus, or here at COSMIC, or here at DepMap portal.
The tables below were derived using the data mining tools on the SLKBase and are designed to provide summaries of the oncogene signature of this cell line, and the best druggable targets for these cells.
Oncogene Signature: This oncogene signature shows the ERBB2 amplification that was a hit in both functional screens. The signature also shows the AURKA amplification, which was also a hit in the screen. AURKA is highlighted in blue because it is a common essential gene in the CRISPR screen. That is, the gene was determined to be an essential gene in every cell line tested regardless of the genomic status of the gene. (For a discussion of the importance of common essential genes identified in CRISPR and RNAi screens, see my recent blog here. ) ERBB2, SMARCE1, and RARA are highlighted in red as these are considered to be bone fide oncogenes that, in this cell line, have a genomic alteration and were hits in at lease one of the screens. The remaining genes in this signature are also considered to be bone fide oncogenes and are genomically altered in this cell line, but these genes were not found to be essential in either the CRISPR or the RNAi based screens. The mutation in TP53 is highlighted in green as this gene is likely to act as a tumor suppressor, and this particular mutation is a common occurrence in the COSMIC data base.
| Gene | CRISPR score | Demeter score | Log fold change | DNA amp | mutation | occ. In Cosmic |
| AURKA | -1.183754842 | -0.501279846 | 1.008134689 | 1.2272 | ||
| ERBB2 | -0.81489376 | -0.495464868 | 5.854488474 | 3.3439 | ||
| SMARCE1 | -0.598356409 | -0.325203546 | 1.18256134 | 1.3173 | ||
| RARA | -0.586624882 | -0.274944017 | 1.694201401 | 2.5639 | ||
| ELOC | -0.403087242 | -0.178813499 | 1.138643654 | 1.6797 | ||
| STAT5B | -0.27649458 | -0.095157572 | 1.17443238 | 1.1702 | ||
| CDK12 | -0.26279802 | -0.601352907 | 3.794774569 | 3.3439 | ||
| NBN | -0.201977602 | -0.152043073 | 2.793320834 | 3.1267 | ||
| TP53 | -0.053726893 | -0.27903056 | -0.225134963 | -0.1693 | p.R175H | 980 |
| STAT3 | -0.032689981 | 0.000587113 | 1.727727737 | 1.1702 | ||
| SOCS1 | 0.076245639 | 0.235202929 | 0.479619446 | 0.1428 | p.L73L | 5 |
| SMAD4 | 0.190983119 | 0.005478348 | -2.609086904 | -0.8539 | p.D355N | 29 |
| IKZF1 | 0.354148805 | -0.112387223 | -0.02774499 | 0.8119 | p.G106V | 331 |
The best targets druggable signature for AU565:
It is clear from the Tier 1 druggable targets that for this cell line, ERBB2 is a driving oncogene that was essential in the screens and renders the cells highly sensitive to several different ERBB2 targeted drugs. It’s particularly interesting that these cells are highly sensitive to Lapatinib, as not all ERBB2 amplified lines that show sensitivity to the pure ERBB2 inhibitor CP724714 also show sensitivity to less selective inhibitors. In Tier 2, there are several genes that were hits in the screen and which are associated with sensitivity to targeted drugs, and interestingly, most of these are in the signaling pathway driven by ERBB2 activation. Finally, Tier 3 shows that the cells are sensitive to several other drugs that target genes closely related to ERBB2, even though these genes were not screen hits. In addition to that though, the cells show sensitivity to drugs that target TNKS/TNKS2 as well as PORCN, and based on Tier 3 criteria (see the blog) we feel that these drug sensitivities reflect on-target activity, and thus are correct. Given that, the AU565 cell line is rich with druggable targets and many different combinations could be possible using low concentrations or different targeted drugs.
| Tier1: AU565 | ||||||||
| Drug name | Gene symbol_HGNC | z_score_GDSC1 | z_score_GDSC2 | DNA_amp | lfc | mutation | COSMIC_hit | |
| Lapatinib | ERBB2 | 0 | -2.145526 | 3.3439 | 5.854488474 | NULL | 0 | |
| Afatinib | ERBB2 | -2.364684 | -2.035281 | 3.3439 | 5.854488474 | NULL | 0 | |
| Sapitinib | ERBB2 | 0 | -1.682239 | 3.3439 | 5.854488474 | NULL | 0 | |
| CP724714 | ERBB2 | -3.095289 | 0 | 3.3439 | 5.854488474 | NULL | 0 | |
| CI-1033 | ERBB2 | -3.460803 | 0 | 3.3439 | 5.854488474 | NULL | 0 | |
| PF-00299804 | ERBB2 | -3.999264 | 0 | 3.3439 | 5.854488474 | NULL | 0 | |
| Tier2: AU565 | ||||||||
| Drug name | Gene symbol_HGNC | z_score_GDSC1 | z_score_GDSC2 | DNA_amp | lfc | mutation | achilles_score | demeter |
| Rapamycin | MTOR | 0 | -2.082992 | -0.1194 | 0.095132459 | NULL | -1.301219832 | -0.917731707 |
| AT13148 | AKT1 | 0 | -1.930824 | 0.3319 | 0.652507231 | NULL | -0.198463775 | -0.537905343 |
| Uprosertib | AKT1 | 0 | -1.701098 | 0.3319 | 0.652507231 | NULL | -0.198463775 | -0.537905343 |
| Sapitinib | ERBB3 | 0 | -1.682239 | 0.0815 | 0.895966234 | p.E952Q | -1.047871935 | -0.870693342 |
| AKT inhibitor VIII | AKT1 | -2.250084 | 0 | 0.3319 | 0.652507231 | NULL | -0.198463775 | -0.537905343 |
| Tier3: AU565 | ||||||||
| Drug Name | Gene SymbolHGNC | z_score_GDSC1 | z_score_GDSC2 | DNA_amp | lfc | mutation | achilles_score | demeter |
| MN-64 | TNKS | 0 | -2.620924 | -0.7706 | -0.033519801 | NULL | -0.160955435 | -0.214222869 |
| MN-64 | TNKS2 | 0 | -2.620924 | -0.7996 | -0.389591804 | NULL | -0.175249976 | -0.202173515 |
| Lapatinib | EGFR | 0 | -2.145526 | 0.8119 | 1.361440138 | p.R309G | 0.07931304 | -0.08454952 |
| Afatinib | EGFR | -2.364684 | -2.035281 | 0.8119 | 1.361440138 | p.R309G | 0.07931304 | -0.08454952 |
| GSK1904529A | IGF1R | -2.297279 | -1.670365 | -0.2683 | -0.571973914 | NULL | 0.103843149 | -0.001585228 |
| GSK1904529A | INSR | -2.297279 | -1.670365 | -0.6802 | -0.470097197 | p.V615F | -0.044696116 | 0.013883225 |
| LGK974 | PORCN | -2.52058 | -0.541474 | 0.5131 | 0.02713613 | NULL | 0.240630376 | 0.15117195 |
| Wnt-C59 | PORCN | -2.355176 | -0.130387 | 0.5131 | 0.02713613 | NULL | 0.240630376 | 0.15117195 |
| AKT inhibitor VIII | AKT1 | -2.250084 | 0 | 0.3319 | 0.652507231 | NULL | -0.198463775 | -0.537905343 |
| AKT inhibitor VIII | AKT2 | -2.250084 | 0 | -0.244 | -0.324320939 | NULL | -0.341700871 | -0.42961282 |
| AKT inhibitor VIII | AKT3 | -2.250084 | 0 | 0.0732 | -1.494182941 | NULL | 0.076937914 | 0.108775863 |
| CI-1033 | EGFR | -3.460803 | 0 | 0.8119 | 1.361440138 | p.R309G | 0.07931304 | -0.08454952 |
| PF-00299804 | EGFR | -3.999264 | 0 | 0.8119 | 1.361440138 | p.R309G | 0.07931304 | -0.08454952 |
| AST-1306 | EGFR | -3.801252 | 0 | 0.8119 | 1.361440138 | p.R309G | 0.07931304 | -0.08454952 |
| CI-1033 | ERBB4 | -3.460803 | 0 | -0.3226 | -0.129676307 | NULL | -0.081479023 | -0.091483524 |
| PF-00299804 | ERBB4 | -3.999264 | 0 | -0.3226 | -0.129676307 | NULL | -0.081479023 | -0.091483524 |
| AST-1306 | ERBB4 | -3.801252 | 0 | -0.3226 | -0.129676307 | NULL | -0.081479023 | -0.091483524 |
