TY - JOUR
T1 - Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response
AU - Jernström, Sandra
AU - Hongisto, Vesa
AU - Leivonen, Suvi
AU - Due, Eldri
AU - Tadele, Dagim
AU - Edgren, Henrik
AU - Kallioniemi, Olli
AU - Perälä, Merja
AU - Mælandsmo, Gunhild
AU - Sahlberg, Kristine
PY - 2017/3/21
Y1 - 2017/3/21
N2 - Background: Approximately 15%-20% of all diagnosed breast
cancers are characterized by amplified and overexpressed
HER2 (= ErbB2). These breast cancers are aggressive and
have a poor prognosis. Although improvements in treatment
have been achieved after the introduction of trastuzumab
and lapatinib, many patients do not benefit from these
drugs. Therefore, in-depth understanding of the
mechanisms behind the treatment responses is essential to
find alternative therapeutic strategies. Materials and
methods: Thirteen HER2 positive breast cancer cell lines
were screened with 22 commercially available compounds,
mainly targeting proteins in the ErbB2-signaling pathway,
and molecular mechanisms related to treatment sensitivity
were sought. Cell viability was measured, and treatment
responses between the cell lines were compared. To search
for response predictors and genomic and transcriptomic
profiling, PIK3CA mutations and PTEN status were explored
and molecular features associated with drug sensitivity
sought. Results: The cell lines were divided into three
groups according to the growth-retarding effect induced
by trastuzumab and lapatinib. Interestingly, two cell
lines insensitive to trastuzumab (KPL4 and SUM190PT)
showed sensitivity to an Akt1/2 kinase inhibitor. These
cell lines had mutation in PIK3CA and loss of PTEN,
suggesting an activated and druggable Akt-signaling
pathway. Expression levels of five genes (CDC42, MAPK8,
PLCG1, PTK6, and PAK6) were suggested as predictors for
the Akt1/2 kinase-inhibitor response. Conclusion:
Targeting the Akt-signaling pathway shows promise in cell
lines that do not respond to trastuzumab. In addition,
our results indicate that several molecular features
determine the growth-retarding effects induced by the
drugs, suggesting that parameters other than HER2
amplification/expression should be included as markers
for therapy decisions.
AB - Background: Approximately 15%-20% of all diagnosed breast
cancers are characterized by amplified and overexpressed
HER2 (= ErbB2). These breast cancers are aggressive and
have a poor prognosis. Although improvements in treatment
have been achieved after the introduction of trastuzumab
and lapatinib, many patients do not benefit from these
drugs. Therefore, in-depth understanding of the
mechanisms behind the treatment responses is essential to
find alternative therapeutic strategies. Materials and
methods: Thirteen HER2 positive breast cancer cell lines
were screened with 22 commercially available compounds,
mainly targeting proteins in the ErbB2-signaling pathway,
and molecular mechanisms related to treatment sensitivity
were sought. Cell viability was measured, and treatment
responses between the cell lines were compared. To search
for response predictors and genomic and transcriptomic
profiling, PIK3CA mutations and PTEN status were explored
and molecular features associated with drug sensitivity
sought. Results: The cell lines were divided into three
groups according to the growth-retarding effect induced
by trastuzumab and lapatinib. Interestingly, two cell
lines insensitive to trastuzumab (KPL4 and SUM190PT)
showed sensitivity to an Akt1/2 kinase inhibitor. These
cell lines had mutation in PIK3CA and loss of PTEN,
suggesting an activated and druggable Akt-signaling
pathway. Expression levels of five genes (CDC42, MAPK8,
PLCG1, PTK6, and PAK6) were suggested as predictors for
the Akt1/2 kinase-inhibitor response. Conclusion:
Targeting the Akt-signaling pathway shows promise in cell
lines that do not respond to trastuzumab. In addition,
our results indicate that several molecular features
determine the growth-retarding effects induced by the
drugs, suggesting that parameters other than HER2
amplification/expression should be included as markers
for therapy decisions.
KW - drug screening
KW - ErbB2
KW - gene expression
KW - pharmacogenomics
KW - predictors
UR - http://www.scopus.com/inward/record.url?scp=85016166061&partnerID=8YFLogxK
U2 - 10.2147/BCTT.S115600
DO - 10.2147/BCTT.S115600
M3 - Article
VL - 9
SP - 185
EP - 198
JO - Breast Cancer
JF - Breast Cancer
SN - 1179-1314
M1 - A22
ER -