The HCC1419 Breast Cancer Cell Line

The HCC1419 breast cancer cell line was derived from the primary ductal carcinoma a 42 year old female of European-American and Native American decent.  The cell line is a ER-positive and ERBB2 positive cell line with a HER2 (ERBB2) gene amplification.  The STR profile along with links to the complete genomic data on these cells can be found at Cellosaurus, at COSMIC, and at the DepMap Portal.

Oncogene Signature:

As indicated above, HCC1419 is a HER2 amplified breast cancer cell line and as shown below, ERBB2 is amplified, overexpressed and was a strong hit in the functional screen.  And as also indicated above, this is an ER* positive cell line and indeed, ESR1 is highly overexpressed in these cells and this gene also was a strong hit in the screen.  There are other very interesting features of this cell line beyond the ER and HER2 status.  As shown below, these cells have an amplification and overexpression of MYC, which is an essential gene in these cells, and they have a TP53 mutation, but in these cells the gene was a hit in the screen suggesting strongly that in these cells, TP53 has dominant (negative?) activity.  AURKA is amplified and overexpressed in these cells, but keep in mind that this gene is a common essential in the CRISPR screens.  It is particularly interesting that TOP1 is amplified in this cell line.  The amplification itself is not too surprising since the gene is close to the ERBB2 gene, but it’s essentiality in the CRISPR screen is of interest and may have implications for drug sensitivity.

Gene CRISPR score Demeter score Log fold change DNA amp mutation occ. In Cosmic
MYC -1.911438115 -2.113827675 1.9244
ERBB2 -1.351421217 5.858527326 4.189
AURKA -1.29952235 2.167792194 2.1947
ESR1 -1.17260532 2.653920144 0.1656
GNAS -0.914246691 1.468668746 2.1761
RAD21 -0.914131223 1.945516826 2.3296
TOP1 -0.830755533 1.457295072 1.0835
TP53 -0.624734054 -0.92510281 -0.312 p.Y220C, p.APA74fs 29
RXRA -0.311641962 1.12793718 1.1889
RTEL1 -0.263489279 1.70966697 2.9093
NBN -0.261784231 1.389463359 1.5407
RUNX1T1 -0.216511318 1.23878686 1.5251
PTPN1 -0.187973879 1.892709783 2.1995
FLCN -0.159013654 2.127542733 1.5249
SPOP -0.101746009 2.579147403 2.8946
AGO2 -0.090880833 1.41276091 1.9206
MAFB -0.066136286 -1.152712309 1.0835
SRC -0.062508309 -1.306573717 1.0835
RECQL4 2.133887789 2.9291

*The ESR1 gene is actually not considered an oncogene in the OncoKB data base.  I added it to this signature because this is one of those cell lines where the gene is highly overexpressed and essential, so this is clearly acting like a breast cancer oncogene.

HCC1419 Drug Sensitivities.  As a breast cancer cell line that is both ER overexpressing and HER2 amplified and overexpressed, this cell line is rich with druggable targets.  As shown in Tier 1, the cells are highly sensitive to both ER and HER2 targeted drugs, and this not always the case in cells with both druggable targets present, as it has been observed that the presence of amplified HER2 renders cells resistant to ER-targeted drugs, but that is not the case with this cell line.  Interestingly, the RET oncogene, while not amplified, is highly overexpressed in this cell line and the cells are sensitive to the RET specific drug Motesanib.  Tier 2 presents yet another druggable target as the WDR48 gene was both a hit in the screen and renders the cells sensitive to it’s targeted drug ML323.   Tier 3 shows additional drugs to which the cells are highly sensitive and these drugs make the Tier 3 list because they are less specific drugs that target ERBB2 and other ERBB family members, and Motesanib is on the Tier 3 list because it has other targets besides RET, and since none of the target genes are amplified, this drug does make the Tier 3 list too.  It is noteworthy and not surprising that the cells are moderately sensitive to MK2206 that targets all AKT isoforms, and Doramapimod that targets MAPK14 and MAPK9.  The Z-scores for these drugs are less than -1.5 but not less than -2.0.

HCC1419.T1
Drug name Gene symbol_HGNC z_score_GDSC1 z_score_GDSC2 DNA_amp lfc mutation COSMIC_hit
GDC0810 ESR1 0 -1.884934 0.1656 2.653920144 NULL 0
Motesanib RET -2.204144 0 -0.0964 2.958744798 NULL 0
PF-00299804 ERBB2 -2.911448 0 4.189 5.858527326 NULL 0
CI-1033 ERBB2 -2.464143 0 4.189 5.858527326 NULL 0
CP724714 ERBB2 -3.134253 0 4.189 5.858527326 NULL 0
HCC1419.T2
Drug name Gene symbol_HGNC z_score_GDSC1 z_score_GDSC2 DNA_amp lfc mutation COSMIC_hit achilles_score demeter
GDC0810 ESR1 0 -1.884934 0.1656 2.653920144 NULL 0 -1.17260532 NULL
ML323 WDR48 0 -1.574182 0.1236 0.444018966 NULL 0 -0.926235754 NULL
HCC1419.T3
Drug name Gene SymbolHGNC z_score_GDSC1 z_score_GDSC2 DNA_amp lfc mutation COSMIC_hit achilles_score demeter
CI-1033 EGFR -2.464143 0 0.3076 -3.579209641 NULL 0 0.154432175 NULL
PF-00299804 EGFR -2.911448 0 0.3076 -3.579209641 NULL 0 0.154432175 NULL
AST-1306 EGFR -2.930609 0 0.3076 -3.579209641 NULL 0 0.154432175 NULL
CI-1033 ERBB4 -2.464143 0 -0.2003 1.996747056 NULL 0 -0.165461749 NULL
PF-00299804 ERBB4 -2.911448 0 -0.2003 1.996747056 NULL 0 -0.165461749 NULL
AST-1306 ERBB4 -2.930609 0 -0.2003 1.996747056 NULL 0 -0.165461749 NULL
Motesanib KDR -2.204144 0 0.1337 -0.013939191 NULL 0 0.019017614 NULL
Motesanib KIT -2.204144 0 0.1337 0.059177678 NULL 0 -0.266232889 NULL
Motesanib PDGFRA -2.204144 0 0.1337 -0.041027268 NULL 0 -0.199950124 NULL
Motesanib PDGFRB -2.204144 0 -0.3102 -0.187278568 NULL 0 0.029946875 NULL
Motesanib RET -2.204144 0 -0.0964 2.958744798 NULL 0 0.062279488 NULL