PMID- 20453058
OWN - NLM
STAT- MEDLINE
DCOM- 20101220
LR  - 20220316
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 16
IP  - 14
DP  - 2010 Jul 15
TI  - Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase 
      inhibitor GDC-0941 in breast cancer preclinical models.
PG  - 3670-83
LID - 10.1158/1078-0432.CCR-09-2828 [doi]
AB  - PURPOSE: 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. EXPERIMENTAL DESIGN: 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. 
      CONCLUSION: 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.
CI  - Copyright 2010 AACR.
FAU - O'Brien, Carol
AU  - O'Brien C
AD  - Department of Development Oncology Diagnostics, Genentech, Inc., South San 
      Francisco, California 94080, USA.
FAU - Wallin, Jeffrey J
AU  - Wallin JJ
FAU - Sampath, Deepak
AU  - Sampath D
FAU - GuhaThakurta, Debraj
AU  - GuhaThakurta D
FAU - Savage, Heidi
AU  - Savage H
FAU - Punnoose, Elizabeth A
AU  - Punnoose EA
FAU - Guan, Jane
AU  - Guan J
FAU - Berry, Leanne
AU  - Berry L
FAU - Prior, Wei Wei
AU  - Prior WW
FAU - Amler, Lukas C
AU  - Amler LC
FAU - Belvin, Marcia
AU  - Belvin M
FAU - Friedman, Lori S
AU  - Friedman LS
FAU - Lackner, Mark R
AU  - Lackner MR
LA  - eng
PT  - Journal Article
DEP - 20100507
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 
      (2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Indazoles)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Sulfonamides)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
SB  - IM
EIN - Clin Cancer Res. 2011 Apr 1;17(7):2066-7
CIN - Clin Cancer Res. 2010 Jul 15;16(14):3523-5. PMID: 20538763
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Biomarkers, Tumor/antagonists & inhibitors/genetics/metabolism
MH  - Breast Neoplasms/*drug therapy/genetics/metabolism
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - *Disease Models, Animal
MH  - Female
MH  - Gene Expression Profiling
MH  - Humans
MH  - Indazoles/*pharmacology
MH  - Mammary Neoplasms, Experimental/*drug therapy/genetics/metabolism
MH  - Mice
MH  - Mutation
MH  - Neoplasm Transplantation
MH  - Oligonucleotide Array Sequence Analysis
MH  - Phosphatidylinositol 3-Kinase/genetics/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Predictive Value of Tests
MH  - Receptor, ErbB-2/antagonists & inhibitors/genetics
MH  - Sensitivity and Specificity
MH  - Sulfonamides/*pharmacology
MH  - Xenograft Model Antitumor Assays
EDAT- 2010/05/11 06:00
MHDA- 2010/12/21 06:00
CRDT- 2010/05/11 06:00
PHST- 2010/05/11 06:00 [entrez]
PHST- 2010/05/11 06:00 [pubmed]
PHST- 2010/12/21 06:00 [medline]
AID - 1078-0432.CCR-09-2828 [pii]
AID - 10.1158/1078-0432.CCR-09-2828 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2010 Jul 15;16(14):3670-83. doi: 10.1158/1078-0432.CCR-09-2828. 
      Epub 2010 May 7.