Identification of expression signatures predictive of sensitivity to the Bcl-2 family member inhibitor ABT-263 in small cell lung carcinoma and leukemia/lymphoma cell lines.
ABT-263 inhibits the antiapoptotic proteins Bcl-2, Bcl-x(L), and Bcl-w and has single-agent efficacy in numerous small cell lung carcinoma (SCLC) and leukemia/lymphoma cell lines in vitro and in vivo. It is currently in clinical trials for treating patients with SCLC and various leukemia/lymphomas. Identification of predictive markers for response will benefit the clinical development of ABT-263. We identified the expression of Bcl-2 family genes that correlated best with sensitivity to ABT-263 in a panel of 36 SCLC and 31 leukemia/lymphoma cell lines. In cells sensitive to ABT-263, expression of Bcl-2 and Noxa is elevated, whereas expression of Mcl-1 is higher in resistant cells. We also examined global expression differences to identify gene signature sets that correlated with sensitivity to ABT-263 to generate optimal signature sets predictive of sensitivity to ABT-263. Independent cell lines were used to verify the predictive power of the gene sets and to refine the optimal gene signatures. When comparing normal lung tissue and SCLC primary tumors, the expression pattern of these genes in the tumor tissue is most similar to sensitive SCLC lines, whereas normal tissue is most similar to resistant SCLC lines. Most of the genes identified using global expression patterns are related to the apoptotic pathway; however, all but Bcl-rambo are distinct from the Bcl-2 family. This study leverages global expression data to identify key gene expression patterns for sensitivity to ABT-263 in SCLC and leukemia/lymphoma and may provide guidance in the selection of patients in future clinical trials.
Tahir
Stephen K
SK
Global Pharmaceutical Product Research Division, Abbott Laboratories, Abbott Park, Illinois 60064-6099, USA.
Wass
John
J
Joseph
Mary K
MK
Devanarayan
Viswanath
V
Hessler
Paul
P
Zhang
Haichao
H
Elmore
Steve W
SW
Kroeger
Paul E
PE
Tse
Christin
C
Rosenberg
Saul H
SH
Anderson
Mark G
MG
D000814:Aniline Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000032:analysis* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005810:Multigene Family / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C528561:navitoclax