Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models.
OBJECTIVE
The class I phosphatidylinositol 3' kinase (PI3K) plays a major role in proliferation and survival in a wide variety of human cancers. A key factor in successful development of drugs targeting this pathway is likely to be the identification of responsive patient populations with predictive diagnostic biomarkers. This study sought to identify candidate biomarkers of response to the selective PI3K inhibitor GDC-0941.


METHODS
We used a large panel of breast cancer cell lines and in vivo xenograft models to identify candidate predictive biomarkers for a selective inhibitor of class I PI3K that is currently in clinical development. The approach involved pharmacogenomic profiling as well as analysis of gene expression data sets from cells profiled at baseline or after GDC-0941 treatment.


RESULTS
We found that models harboring mutations in PIK3CA, amplification of human epidermal growth factor receptor 2, or dual alterations in two pathway components were exquisitely sensitive to the antitumor effects of GDC-0941. We found that several models that do not harbor these alterations also showed sensitivity, suggesting a need for additional diagnostic markers. Gene expression studies identified a collection of genes whose expression was associated with in vitro sensitivity to GDC-0941, and expression of a subset of these genes was found to be intimately linked to signaling through the pathway.


CONCLUSIONS
Pathway focused biomarkers and the gene expression signature described in this study may have utility in the identification of patients likely to benefit from therapy with a selective PI3K inhibitor.
O'Brien
Carol
C
Department of Development Oncology Diagnostics, Genentech, Inc., South San Francisco, California 94080, USA.
Wallin
Jeffrey J
JJ
Sampath
Deepak
D
GuhaThakurta
Debraj
D
Savage
Heidi
H
Punnoose
Elizabeth A
EA
Guan
Jane
J
Berry
Leanne
L
Prior
Wei Wei
WW
Amler
Lukas C
LC
Belvin
Marcia
M
Friedman
Lori S
LS
Lackner
Mark R
MR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011237:Predictive Value of Tests; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D012680:Sensitivity and Specificity; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D007191:Indazoles; D058539:Phosphatidylinositol 3-Kinase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D013449:Sulfonamides; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C508053:ERBB2 protein, human