Profiles of Basal and stimulated receptor signaling networks predict drug response in breast cancer lines.
Identifying factors responsible for variation in drug response is essential for the effective use of targeted therapeutics. We profiled signaling pathway activity in a collection of breast cancer cell lines before and after stimulation with physiologically relevant ligands, which revealed the variability in network activity among cells of known genotype and molecular subtype. Despite the receptor-based classification of breast cancer subtypes, we found that the abundance and activity of signaling proteins in unstimulated cells (basal profile), as well as the activity of proteins in stimulated cells (signaling profile), varied within each subtype. Using a partial least-squares regression approach, we constructed models that significantly predicted sensitivity to 23 targeted therapeutics. For example, one model showed that the response to the growth factor receptor ligand heregulin effectively predicted the sensitivity of cells to drugs targeting the cell survival pathway mediated by PI3K (phosphoinositide 3-kinase) and Akt, whereas the abundance of Akt or the mutational status of the enzymes in the pathway did not. Thus, basal and signaling protein profiles may yield new biomarkers of drug sensitivity and enable the identification of appropriate therapies in cancers characterized by similar functional dysregulation of signaling networks.
HMS LINCS Center Department of Systems Biology Harvard Medical School Boston, Massachusetts 02115, USA.
Mario
M
Niepel
HMS LINCS Center Department of Systems Biology Harvard Medical School Boston, Massachusetts 02115, USA.
Marc
M
Hafner
Merrimack Pharmaceuticals Cambridge, MA 02139, USA.
Emily A
EA
Pace
HMS LINCS Center Department of Systems Biology Harvard Medical School Boston, Massachusetts 02115, USA.
Mirra
M
Chung
Merrimack Pharmaceuticals Cambridge, MA 02139, USA.
Diana H
DH
Chai
HMS LINCS Center Department of Systems Biology Harvard Medical School Boston, Massachusetts 02115, USA.
Lili
L
Zhou
Merrimack Pharmaceuticals Cambridge, MA 02139, USA.
Birgit
B
Schoeberl
HMS LINCS Center Department of Systems Biology Harvard Medical School Boston, Massachusetts 02115, USA.
Peter K
PK
Sorger
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009154:Mutation; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C094131:NRG1 protein, human; D020890:Neuregulin-1; D017978:Receptors, Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt