PMID- 20682712
OWN - NLM
STAT- MEDLINE
DCOM- 20101202
LR  - 20211020
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 16
IP  - 16
DP  - 2010 Aug 15
TI  - Gene array and fluorescence in situ hybridization biomarkers of activity of 
      saracatinib (AZD0530), a Src inhibitor, in a preclinical model of colorectal 
      cancer.
PG  - 4165-77
LID - 10.1158/1078-0432.CCR-10-0066 [doi]
AB  - PURPOSE: To evaluate the efficacy of saracatinib (AZD0530), an oral Src 
      inhibitor, in colorectal cancer (CRC) and to identify biomarkers that predict 
      antitumor activity. EXPERIMENTAL DESIGN: Twenty-three CRC cell lines were exposed 
      to saracatinib, and baseline gene expression profiles of three sensitive and 
      eight resistant cell lines in vitro and in vivo were used to predict saracatinib 
      sensitivity in an independent group of 10 human CRC explant tumors using the gene 
      array K-Top Scoring Pairs (K-TSP) method. In addition, fluorescence in situ 
      hybridization (FISH) and immunoblotting determined both Src gene copy number and 
      activation of Src, respectively. RESULTS: Two of 10 explant tumors were 
      determined to be sensitive to saracatinib. The K-TSP classifier (TOX>GLIS2, 
      TSPAN7>BCAS4, and PARD6G>NXN) achieved 70% (7 of 10) accuracy on the test set. 
      Evaluation of Src gene copy number by FISH showed a trend toward significance (P 
      = 0.066) with respect to an increase in Src gene copy and resistance to 
      saracatinib. Tumors sensitive to saracatinib showed an increase in the activation 
      of Src and FAK when compared with resistant tumors. CONCLUSIONS: Saracatinib 
      significantly decreased tumor growth in a subset of CRC cell lines and explants. 
      A K-TSP classifier (TOX>GLIS2, TSPAN7>BCAS4, and PARD6G>NXN) was predictive for 
      sensitivity to saracatinib. In addition, increased activation of the Src pathway 
      was associated with sensitivity to saracatinib. These results suggest that FISH, 
      a K-TSP classifier, and activation of the Src pathway have potential in 
      identifying CRC patients that would potentially benefit from treatment with 
      saracatinib.
FAU - Arcaroli, John J
AU  - Arcaroli JJ
AD  - Division of Medical Oncology, University of Colorado, Denver, Colorado, USA.
FAU - Touban, Basel M
AU  - Touban BM
FAU - Tan, Aik Choon
AU  - Tan AC
FAU - Varella-Garcia, Marileila
AU  - Varella-Garcia M
FAU - Powell, Rebecca W
AU  - Powell RW
FAU - Eckhardt, S Gail
AU  - Eckhardt SG
FAU - Elvin, Paul
AU  - Elvin P
FAU - Gao, Dexiang
AU  - Gao D
FAU - Messersmith, Wells A
AU  - Messersmith WA
LA  - eng
GR  - R01 CA152303/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20100803
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 (Antineoplastic Agents)
RN  - 0 (Benzodioxoles)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 9KD24QGH76 (saracatinib)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Benzodioxoles/*pharmacology
MH  - Biomarkers, Tumor/analysis
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Separation
MH  - Colorectal Neoplasms/*drug therapy/genetics
MH  - Drug Resistance, Neoplasm/*genetics
MH  - Flow Cytometry
MH  - Humans
MH  - Immunoblotting
MH  - Immunohistochemistry
MH  - In Situ Hybridization, Fluorescence
MH  - Mice
MH  - Oligonucleotide Array Sequence Analysis
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Quinazolines/*pharmacology
MH  - Xenograft Model Antitumor Assays
PMC - PMC3805460
MID - NIHMS504902
COIS- Disclosure of Potential Conflicts of Interest J.J. Arcoli: advisory board for 
      saracatinib, AstraZeneca. The other authors disclosed no potential conflicts of 
      interest.
EDAT- 2010/08/05 06:00
MHDA- 2010/12/14 06:00
PMCR- 2013/10/22
CRDT- 2010/08/05 06:00
PHST- 2010/08/05 06:00 [entrez]
PHST- 2010/08/05 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
PHST- 2013/10/22 00:00 [pmc-release]
AID - 1078-0432.CCR-10-0066 [pii]
AID - 10.1158/1078-0432.CCR-10-0066 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2010 Aug 15;16(16):4165-77. doi: 10.1158/1078-0432.CCR-10-0066. 
      Epub 2010 Aug 3.