CAL51 cell line is a triple negative breast cancer cell line of the Basal B subtype that was derived from the pleural effusion metastasis of a 45 year old Caucasian female patient previously diagnosed with breast carcinoma. The STR profile for this cell line along with links to genomics resources pertinent to this cell line can be found at Cellosaurus, or here at COSMIC, or here at DepMap portal.
Oncogene Signature: Even though CAL51 is a Basal B triple negative breast cancer cell line, it bears some genomic features more commonly associated with luminal breast cancers. Specifically, these cells exhibit a PIK3CA mutation that is common in luminal and ER+ breast cancer, but less common in basal breast cancers. The CRISPR and RNAi screening data both point to the mutant PIK3CA as an essential gene, which predicts sensitivity to Class I-alpha-specific PI3’Kinase drugs such as Alpelisib, though the PTEN mutation could have an influence on the cells sensitivity to that drug (see below). Interestingly, in addition to the PIK3CA mutation, the cells have two distinct PTEN mutations which don’t affect the expression level of the gene at the mRNA level. Thus, these cells have mutations in two genes that drive the constitutive activity of the PI3’K-AKT pathway. The cells also have recurrent, but fairly uncommon mutation in MAX, and this gene was also a screen hit. The finding that MAX is both mutant and essential in this cell line is highly suggestive of this cell line being a MYC driven line, which is consistent with its Basal B expression profile. There are also mutations in STK11 which was a hit in the CRISPR screen but not the RNAi screen, and MAP2K4, which was not a hit in either screen. Thus, this is an interesting constellation of point mutations that have implications for the targeted drug strategies outlined below.
| Gene | CRISPR score | Demeter score | Log fold change | DNA amp | mutation | occ. In Cosmic |
| PIK3CA | -1.03325346 | -0.680618812 | -0.328897843 | 0.0232 | p.E542K | 555 |
| MAX | -0.670005653 | -0.804908203 | -0.844536097 | -0.0198 | p.R51Q | 5 |
| STK11 | -0.62147787 | -0.150040259 | 0.697187638 | -0.0277 | p.S193S | 28 |
| MAP2K4 | 0.024070069 | 0.075578597 | 0.345055705 | -0.0171 | p.G265D | 7 |
| PTEN | 0.280704695 | 0.008640133 | 0.084941403 | -0.0019 | p.E288fs, p.TK321fs | 58 |
Signature of best druggable targets in this cell line: The first thing that one notices when looking at the the tables below is that there are not Tier 1 drug sensitivities reported, despite the fact that PIK3CA is mutant and essential in this cell line. If one refers to the Functional Druggable Signature tool for this cell line, it can be seen that the cells did not exhibit sufficient sensitivity to any PI3’Kinase targeted drug to make the cut for Tier 1. This suggests that the PTEN mutations in combination with the PIK3CA mutations have a significant impact on the sensitivity to the drugs that target this essential gene.
Regarding Tier 2 drug sensitivities, a common observation that we have made in Basal breast cancer cell lines is the finding of key genes in the cell cycle pathway being essential and that essentiality being associated with good drug sensitivity. In this case, ATR, and PLK1 were both found to be essential and the cells exhibited good sensitivity to drugs that target these genes. We have recently shown that PLK1 drug sensitivity is a common feature of basal B breast cancer cells, and these drugs can interact with taxanes to induce cell death in breast cancer cells.
With regard to Tier 3 drug sensitivities, it has been reported that Basal B breast cancer cells often exhibit the phenotype known as BRACness, and thus it is interesting that the lowest Z-score for any targeted drugs in this cell line were for Talazoparib which targets both PARP1 and PARP2. Finally, there are three druggable targets in this cell line that converge on the apoptosis pathway, namely BCL2 (overexpressed in this cell line), PIM1/3 (PIM1 is overexpressed in this cell line) and MCL1, and the cells exhibit good drug sensitivity to drugs that target all three of these gene, but these drugs had Z-scores of approximately -1.4 which isn’t low enough to make our cutpoint for a good Tier 3 drug.
In summary, even though CAL51 is an aggressive Basal B triple negative breast cancer, it actually presents with a some druggable targets to which the cells exhibit moderate to high sensitivity. Thus, there are opportunities for drug combinations, and the possibility of combining a PIK3CA targeted drug with one of the other drugs to which the cells are sensitive is intriguing. Thus, combining cell cycle targeted drugs with taxanes and/or PARP inhibitors could also result in significant synergy. CAL51 is unusual as a triple negative breast cancer cell line in that it provides several targeted therapy opportunities.
| CAL51:Tier1 | ||||||||
| None | ||||||||
| CAL51:Tier2 | ||||||||
| name | symbol_HGNC | z_score_GDSC1 | z_score_GDSC2 | DNA_amp | mutation | lfc | achilles_score | demeter |
| VE-822 | ATR | 0 | -1.8835 | -0.009 | NULL | 0.593725466 | -1.121884643 | -0.370330418 |
| BI-2536 | PLK1 | 0 | -1.745415 | -0.0729 | NULL | 0.320067906 | -1.846172998 | -1.015265491 |
| CAL51:Tier3 | ||||||||
| DrugName | GeneSymbolHGNC | z_score_GDSC1 | z_score_GDSC2 | DNA_amp | lfc | mutation | achilles_score | demeter |
| Talazoparib | PARP1 | -2.15083 | -1.517899 | -0.0244 | 0.464735573 | NULL | -0.19603112 | 0.310871283 |
| Talazoparib | PARP2 | -2.15083 | -1.517899 | -0.0594 | 0.69266731 | NULL | -0.031074904 | NULL |
| Rucaparib | PARP1 | -2.405559 | 0 | -0.0244 | 0.464735573 | NULL | -0.19603112 | 0.310871283 |
| Rucaparib | PARP2 | -2.405559 | 0 | -0.0594 | 0.69266731 | NULL | -0.031074904 | NULL |
