TY - JOUR
T1 - Gene expression signatures and response to imatinib mesylate in gastrointestinal stromal tumor
AU - Rink, Lori
AU - Skorobogatko, Yuliya
AU - Kossenkov, Andrew V.
AU - Belinsky, Martin G.
AU - Pajak, Thomas
AU - Heinrich, Michael C.
AU - Blanke, Charles D.
AU - Von Mehren, Margaret
AU - Ochs, Michael F.
AU - Eisenberg, Burton
AU - Godwin, Andrew K.
PY - 2009/8/1
Y1 - 2009/8/1
N2 - Despite initial efficacy of imatinib mesylate in most gastrointestinal stromal tumor (GIST) patients, many experience primary/secondary drug resistance. Therefore, clinical management of GIST may benefit from further molecular characterization of tumors before and after imatinib mesylate treatment. As part of a recent phase II trial of neoadjuvant/adjuvant imatinib mesylate treatment for advanced primary and recurrent operable GISTs (Radiation Therapy Oncology Group S0132), gene expression profiling using oligonucleotide microarrays was done on tumor samples obtained before and after imatinib mesylate therapy. Patients were classified according to changes in tumor size after treatment based on computed tomography scan measurements. Gene profiling data were evaluated with Statistical Analysis of Microarrays to identify differentially expressed genes (in pretreatment GIST samples). Based on Statistical Analysis of Microarrays [False Discovery Rate (FDR), 10%], 38 genes were expressed at significantly lower levels in the pretreatment biopsy samples from tumors that significantly responded to 8 to 12 weeks of imatinib mesylate, that is, >25% tumor reduction. Eighteen of these genes encoded Krüppel-associated box (KRAB) domain containing zinc finger (ZNF) transcriptional repressors. Importantly, 10 KRAB-ZNF genes mapped to a single locus on chromosome 19p, and a subset predicted likely response to imatinib mesylate-based therapy in a naïve panel of GIST. Furthermore, we found that modifying expression of genes within this predictive signature can enhance the sensitivity of GIST cells to imatinib mesylate. Using clinical pretreatment biopsy samples from a prospective neoadjuvant phase II trial, we have identified a gene signature that includes KRAB-ZNF 91 subfamily members that may be both predictive of and functionally associated with likely response to short-term imatinib mesylate treatment.
AB - Despite initial efficacy of imatinib mesylate in most gastrointestinal stromal tumor (GIST) patients, many experience primary/secondary drug resistance. Therefore, clinical management of GIST may benefit from further molecular characterization of tumors before and after imatinib mesylate treatment. As part of a recent phase II trial of neoadjuvant/adjuvant imatinib mesylate treatment for advanced primary and recurrent operable GISTs (Radiation Therapy Oncology Group S0132), gene expression profiling using oligonucleotide microarrays was done on tumor samples obtained before and after imatinib mesylate therapy. Patients were classified according to changes in tumor size after treatment based on computed tomography scan measurements. Gene profiling data were evaluated with Statistical Analysis of Microarrays to identify differentially expressed genes (in pretreatment GIST samples). Based on Statistical Analysis of Microarrays [False Discovery Rate (FDR), 10%], 38 genes were expressed at significantly lower levels in the pretreatment biopsy samples from tumors that significantly responded to 8 to 12 weeks of imatinib mesylate, that is, >25% tumor reduction. Eighteen of these genes encoded Krüppel-associated box (KRAB) domain containing zinc finger (ZNF) transcriptional repressors. Importantly, 10 KRAB-ZNF genes mapped to a single locus on chromosome 19p, and a subset predicted likely response to imatinib mesylate-based therapy in a naïve panel of GIST. Furthermore, we found that modifying expression of genes within this predictive signature can enhance the sensitivity of GIST cells to imatinib mesylate. Using clinical pretreatment biopsy samples from a prospective neoadjuvant phase II trial, we have identified a gene signature that includes KRAB-ZNF 91 subfamily members that may be both predictive of and functionally associated with likely response to short-term imatinib mesylate treatment.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Antineoplastic Agents/therapeutic use
KW - Benzamides
KW - Female
KW - Gastrointestinal Stromal Tumors/drug therapy
KW - Gene Expression Profiling
KW - Humans
KW - Imatinib Mesylate
KW - Male
KW - Middle Aged
KW - Oligonucleotide Array Sequence Analysis
KW - Piperazines/therapeutic use
KW - Pyrimidines/therapeutic use
KW - Zinc Fingers/genetics
UR - http://www.scopus.com/inward/record.url?scp=68849122493&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000269029300012&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1158/1535-7163.MCT-09-0193
DO - 10.1158/1535-7163.MCT-09-0193
M3 - Article
C2 - 19671739
SN - 1535-7163
VL - 8
SP - 2172
EP - 2182
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 8
ER -