Abstract
| Original language | English |
|---|---|
| Article number | A22 |
| Pages (from-to) | 185-198 |
| Number of pages | 14 |
| Journal | Breast Cancer |
| Volume | 9 |
| DOIs | |
| Publication status | Published - 21 Mar 2017 |
| MoE publication type | A1 Journal article-refereed |
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Keywords
- drug screening
- ErbB2
- gene expression
- pharmacogenomics
- predictors
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Drug-screening and genomic analyses of HER2-positive breast cancer cell lines reveal predictors for treatment response. / Jernström, Sandra; Hongisto, Vesa; Leivonen, Suvi; Due, Eldri; Tadele, Dagim; Edgren, Henrik; Kallioniemi, Olli; Perälä, Merja; Mælandsmo, Gunhild; Sahlberg, Kristine.
In: Breast Cancer, Vol. 9, A22, 21.03.2017, p. 185-198.Research output: Contribution to journal › Article › Scientific › peer-review
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 -