title: Genomic analysis and selective small molecule inhibition identifies BCL-X(L) as a critical survival factor in a subset of colorectal cancer.
abstract: BACKGROUND
  Defects in programmed cell death, or apoptosis, are a hallmark of cancer. The anti-apoptotic B-cell lymphoma 2 (BCL-2) family proteins, including BCL-2, BCL-X(L), and MCL-1 have been characterized as key survival factors in multiple cancer types. Because cancer types with BCL2 and MCL1 amplification are more prone to inhibition of their respectively encoded proteins, we hypothesized that cancers with a significant frequency of BCL2L1 amplification would have greater dependency on BCL-X(L) for survival.
  
  
  METHODS
  To identify tumor subtypes that have significant frequency of BCL2L1 amplification, we performed data mining using The Cancer Genome Atlas (TCGA) database. We then assessed the dependency on BCL-X(L) in a panel of cell lines using a selective and potent BCL-X(L) inhibitor, A-1155463, and BCL2L1 siRNA. Mechanistic studies on the role of BCL-X(L) were further undertaken via a variety of genetic manipulations.
  
  
  RESULTS
  We identified colorectal cancer as having the highest frequency of BCL2L1 amplification across all tumor types examined. Colorectal cancer cell lines with BCL2L1 copy number >3 were more sensitive to A-1155463. Consistently, cell lines with high expression of BCL-XL and NOXA, a pro-apoptotic protein that antagonizes MCL-1 activity were sensitive to A-1155463. Silencing the expression of BCL-X(L) via siRNA killed the cell lines that were sensitive to A-1155463 while having little effect on lines that were resistant. Furthermore, silencing the expression of MCL-1 in resistant cell lines conferred sensitivity to A-1155463, whereas silencing NOXA abrogated sensitivity.
  
  
  CONCLUSIONS
  This work demonstrates the utility of characterizing frequent genomic alterations to identify cancer survival genes. In addition, these studies demonstrate the utility of the highly potent and selective compound A-1155463 for investigating the role of BCL-X(L) in mediating the survival of specific tumor types, and indicate that BCL-X(L) inhibition could be an effective treatment for colorectal tumors with high BCL-X(L) and NOXA expression.
authors.affiliation: Oncology Research, AbbVie, 1 N Waukegan Road, North Chicago, IL, 60064-6101, USA. Haichao.zhang@abbvie.com.
authors.forename: Haichao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Oncology Research, AbbVie, 1 N Waukegan Road, North Chicago, IL, 60064-6101, USA. John.xue@abbvie.com.
authors.forename: John
authors.initials: J
authors.lastname: Xue
authors.affiliation: Oncology Research, AbbVie, 1 N Waukegan Road, North Chicago, IL, 60064-6101, USA. Paul.hessler@abbvie.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Hessler
authors.affiliation: Oncology Research, AbbVie, 1 N Waukegan Road, North Chicago, IL, 60064-6101, USA. Stephen.k.tahir@abbvie.com.
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Tahir
authors.affiliation: Oncology Research, AbbVie, 1 N Waukegan Road, North Chicago, IL, 60064-6101, USA. Jun.chen@abbvie.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Oncology Research, AbbVie, 1 N Waukegan Road, North Chicago, IL, 60064-6101, USA. Sha.jin@abbvie.com.
authors.forename: Sha
authors.initials: S
authors.lastname: Jin
authors.affiliation: Oncology Research, AbbVie, 1 N Waukegan Road, North Chicago, IL, 60064-6101, USA. Andrew.souers@abbvie.com.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
authors.affiliation: Oncology Research, AbbVie, 1 N Waukegan Road, North Chicago, IL, 60064-6101, USA. Joel.leverson@abbvie.com.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Leverson
authors.affiliation: Oncology Research, AbbVie, 1 N Waukegan Road, North Chicago, IL, 60064-6101, USA. Lloyd.Lam@abbvie.com.|Tumor Genomics AP10-214, Department R4CD, 1 North Waukegan Road, North Chicago, IL, 60064-6098, USA. Lloyd.Lam@abbvie.com.
authors.forename: Lloyd T
authors.initials: LT
authors.lastname: Lam
mesh_terms: D052160:Benzothiazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: C000603579:A-1155463; D052160:Benzothiazoles; D007546:Isoquinolines; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein