The CAMA1 breast cancer cell line was derived from the pleural effusion metastasis of an ER+ breast cancer of a 51 year old Caucasian female. Since the cell line was derived from an ER+ breast cancer, it is not surprising that the cells are classified as a luminal breast cancer cell line that overexpresses the ESR1 (estrogen receptor alpha, ERa) gene. The STR profile for this cell line along with links to multiple genomics resources pertinent to this cell line can be found here at Cellosaurus, or here at COSMIC, or here at DepMap Portal.
Oncogene Signature: The Oncogene Signature of this cell line exhibits many classical features of an aggressive luminal ER+ breast cancer cell line. First, the cells highly overexpress the ESR1 gene in the absence of gene amplification, which is a hallmark of this breast cancer subtype. In addition, the cells exhibit the 8p11-p12 region of gene amplification characterized by amplifications of FGFR1, NSD3, and other candidate driver genes. We and others have published extensively on the role of NSD3 as a transforming gene when amplified in breast cancer cells and others have more recently published on the role of this oncogene in squamous lung cancers where this amplicon is also common. In our published work, we and others have associated this genomic region with aggressive luminal breast cancers, and our results point to a role for NSD3 in driving overexpression and constitutive activation of ER-alpha. This region has also gained much interest in recent years because of the presence of FGFR1 which, along with NSD3, is also commonly overexpressed in association with gene amplification. The evidence for FGFR1 as a transforming gene is breast cancer is sparse. Nevertheless, breast cancer patients that overexpress FGFR1 have been enrolled in clinical trials involving drugs that target FGFRs with disappointing results, and indeed, in the CAMA1 cell line, despite the amplification and overexpression of FGFR1, the cells are not sensitive to FGFR-targeted drugs and the gene was not a hit in the functional screen. In addition to these classical genomic alterations associated with luminal breast cancer, these cells have mutations in PTEN and TP53 both of which are consistent with the aggressive nature of these cells. Finally, these cells exhibit low level amplifications of NOTCH2 and RECQL4, neither of which were hits in the CRISPR screen. These cells have also been reported to have a point mutation (c.1712-1G>A) in the CDH1 gene the functional significance of which is unclear since these cells have not been reported to be derived from a lobular breast cancer in which CDH1 inactivating mutations are common.
| Gene | CRISPR score | Demeter score | Log fold change | DNA amp | mutation | occ. In Cosmic |
| ESR1 | -1.090847779 | 3.407229827 | -0.495 | |||
| RBM15 | -0.266905308 | 1.101904125 | 1.3774 | |||
| TP53 | -0.256072801 | 0.109905974 | -0.8154 | p.R280T | 154 | |
| NOTCH2 | -0.085318477 | 1.076891042 | 1.0978 | |||
| FGFR1 | -0.081419623 | 1.130045555 | 1.5798 | |||
| NSD3 | 0.045407059 | 1.949189455 | 1.5798 | |||
| PTEN | 0.30440245 | -0.217435385 | -0.0326 | p.D92H, p.FF278fs | 33 | |
| RECQL4 | 1.270833203 | 1.187 |
Signature of best druggable targets in this cell line: Since this is an ER+ luminal breast cancer cell line, it’s best to start with an evaluation of the hormone receptor based targets expressed in the line, with ESR1 or ER-alpha as the logical starting point. As can be seen in the Tier 1 drug sensitivities below, ESR1 is highly overexpressed in CAMA1 cells and the gene is highly essential as indicated by it’s CRISPR score of -1.9. Thus, it’s not surprising that these cells exhibit exquisite sensitivity to the selective estrogen receptor degrader (SERD) drug GDC0810 with a Z-score of -2.5! It is also interesting that these cells overexpress the androgen receptor (AR) and even though this gene did not score as a hit in the screen, the cells are still highly sensitive to the AR-targeted drug Bicalutamide. The reason for the disconnect between gene essentiality and drug sensitivity for this target is unclear, although the caveat to this observation is that we only have drug sensitivity for Bicalutamide in the GDSC1 data set. We did not identify any drug sensitivities in Tier 2 for this cell line. However, in Tier 3, there are several drug-gene connections showing drug sensitivity which is likely connected to the PTEN mutation in this cell line. The presence of the PTEN mutations may explain their sensitivity of these cells to AZD8186 which targets both PIK3CA and PIK3CB and the Z-scores for this drug in these cells is impressive indeed. Since these cells are wild type for PIK3CA, it’s, therefore, not very surprising that the cells are not highly sensitive to Alpelisib. In addition, the cells exhibit striking sensitivity to a range of AKT targeted drugs, as once again, both AKT1 and AKT2 (but not AKT3) are expressed in these cells. As we have seen previously, when more than one AKT gene is expressed, the sensitivity to drugs that target multiple isoforms is often better than the essentiality scores. In that regard, however, it is interesting that AKT2 came close to scoring as a hit in the CRISPR screen. Thus, the CAMA1 cell line exhibits sensitivity to a number of targeted drugs all of which have Z-scores of less than -2.0, which predicts several different attack strategies that could be used to effectively reverse engineer the malignant properties of this cell line.
| CAMA1:Tier1 | ||||||||
| name | symbol_HGNC | z_score_GDSC1 | z_score_GDSC2 | DNA_amp | lfc | mutation | COSMIC_hit | |
| GDC0810 | ESR1 | 0 | -2.54482 | -0.495 | 3.407229827 | NULL | 0 | |
| Bicalutamide | AR | -2.649815 | 0 | -0.2214 | 3.252704165 | NULL | 0 | |
| CAMA1.Tier2 | ||||||||
| None | ||||||||
| CAMA1.Tier3 | ||||||||
| DrugName | GeneSymbolHGNC | z_score_GDSC1 | z_score_GDSC2 | DNA_amp | lfc | mutation | achilles_score | demeter |
| Afuresertib | AKT1 | 0 | -2.443767 | -0.218 | 0.178240287 | NULL | -0.005863063 | NULL |
| Afuresertib | AKT2 | 0 | -2.443767 | 0.1492 | 0.526143495 | NULL | -0.447763179 | NULL |
| Afuresertib | AKT3 | 0 | -2.443767 | 0.145 | -1.629112521 | NULL | 0.133053653 | NULL |
| Ipatasertib | AKT1 | 0 | -2.3824 | -0.218 | 0.178240287 | NULL | -0.005863063 | NULL |
| Ipatasertib | AKT2 | 0 | -2.3824 | 0.1492 | 0.526143495 | NULL | -0.447763179 | NULL |
| Ipatasertib | AKT3 | 0 | -2.3824 | 0.145 | -1.629112521 | NULL | 0.133053653 | NULL |
| AZD8186 | PIK3CA | 0 | -2.255728 | 0.1353 | 0.352297907 | NULL | -0.329118351 | NULL |
| AZD8186 | PIK3CB | 0 | -2.255728 | 0.1349 | 0.480019956 | NULL | -0.359269624 | NULL |
| AZD5363 | AKT1 | 0 | -2.187212 | -0.218 | 0.178240287 | NULL | -0.005863063 | NULL |
| AZD5363 | AKT2 | 0 | -2.187212 | 0.1492 | 0.526143495 | NULL | -0.447763179 | NULL |
| AZD5363 | AKT3 | 0 | -2.187212 | 0.145 | -1.629112521 | NULL | 0.133053653 | NULL |
| AZD5363 | ROCK2 | 0 | -2.187212 | -0.2485 | -0.260816154 | NULL | -0.029247352 | NULL |
