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Cited by 64Colorectal Cancer Treatments and StudiesCancer Mechanisms and TherapyProtein Kinase Regulation and GTPase Signaling

Gene Array and Fluorescence In situ Hybridization Biomarkers of Activity of Saracatinib (AZD0530), a Src Inhibitor, in a Preclinical Model of Colorectal Cancer

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Arcaroli, John J., Touban, Basel M., Tan, Aik Choon, Varella-Garcia, Marileila, Powell, Rebecca W., Eckhardt, S. Gail, Elvin, Paul, Gao, Dexiang +1 more·2010·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-10-0066PMC PMC3805460
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Abstract

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. Clin Cancer Res; 16(16); OF1–12. ©2010 AACR. Clin Cancer Res; 16(16); 4165–77. ©2010 AACR.

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  • The DOWN gene IGFBP2 was excluded because it appeared not predictive of SRCi sensitivity in CRC cell lines and explant tumors.

    “Notably, the DOWN gene IGFBP2 was excluded here because it appeared to be not predictive of SRCi sensitivity in CRC cell lines and explant tumors [30].”

    From An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy (2022) · cites this paper as [30]

    The Discussion (page not provided) says the LRRC19>IGFBP2 gene pair was tested in the CRC model and was not predictive. It does not establish that IGFBP2 alone was nonpredictive in both CRC cell lines and explant tumors; the explant results concern different gene pairs. The citing authors’ decision to exclude IGFBP2 is their own, rather than a decision attributed to this source. (LLM, conf=0.84)

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Authors
Arcaroli, J. J., Touban, B. M., Tan, A. C., Varella-Garcia, M., Powell, R. W., Eckhardt, S. G., Elvin, P., Gao, D., & Messersmith, W. A.
Affiliations
  • Children's Hospital Colorado (US)
  • Authors' Affiliations: 1Division of Medical Oncology, University of Colorado Denver, and University of Colorado Cancer Center, Anschutz Medical Campus; and 2Gastrointestinal Cancer Program and Experimental Therapeutics Program, University of Colorado Cancer Center, Aurora, Colorado; and 3AstraZeneca, Alderley Park, Macclesfield, United Kingdom, and University of Colorado Denver; Research Institute, The Children's Hospital, Aurora, Colorado
Corresponding author
Messersmith, Wells A.
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2010-08-11
Volume
16
Issue
16
Pages
4165-4177
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-10-0066
PMC
PMC3805460
OpenAlex
W2150310014
Cited by
64
References
8
Citations by year
2026: 3 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 22 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 1 · 2016: 3 · 2015: 3 · 2014: 3 · 2013: 2 · 2012: 8
FWCI
2.06
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R01CA152303)
Topics
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
saracatinib, AZD0530, Src kinase inhibitor, colorectal cancer, predictive biomarkers, drug sensitivity, gene copy number, Src activation, focal adhesion kinase, drug resistance, colorectal cancer cell lines
MeSH terms
Animals, Antineoplastic Agents, Cell Separation, Flow Cytometry, Humans, Immunohistochemistry, Quinazolines, Biomarkers, Tumor, Immunoblotting, Colorectal Neoplasms, Apoptosis, In Situ Hybridization, Fluorescence, Drug Resistance, Neoplasm, Oligonucleotide Array Sequence Analysis, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Mice, Benzodioxoles

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