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Genomic analysis and selective small molecule inhibition identifies BCL-X(L) as a critical survival factor in a subset of colorectal cancer.

Zhang H, Xue J, Hessler P, Tahir SK, Chen J, Jin S, Souers AJ, Leverson JD, Lam LT - Mol. Cancer (2015)

Bottom Line: 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.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.This work demonstrates the utility of characterizing frequent genomic alterations to identify cancer survival genes.

View Article: PubMed Central - PubMed

Affiliation: Oncology Research, AbbVie, 1 N Waukegan Road, North Chicago, IL, 60064-6101, USA. Haichao.zhang@abbvie.com.

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.

No MeSH data available.


Related in: MedlinePlus

Cross-cancer tumor sample analysis identified colorectal cancer as having the highest frequency of BCL2L1 amplification. a Cross-cancer alteration summary for BCL2, BCL2L1 and MCL1 based on data obtained from cBioPortal for Cancer Genomics. b Correlation between gene expression and copy number alteration of BCL2L1 in 212 colorectal cancer samples
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Fig1: Cross-cancer tumor sample analysis identified colorectal cancer as having the highest frequency of BCL2L1 amplification. a Cross-cancer alteration summary for BCL2, BCL2L1 and MCL1 based on data obtained from cBioPortal for Cancer Genomics. b Correlation between gene expression and copy number alteration of BCL2L1 in 212 colorectal cancer samples

Mentions: BCL-XL has been implicated as a key survival factor in numerous solid tumors. Since cancer types with BCL2 and MCL1 amplification are more prone to inhibition of these proteins, we reasoned that significant frequency of BCL2L1 amplification in a particular cancer type may indicate dependency on BCL-XL for survival. To identify cancer types with a significant amplification of BCL2L1, we utilized The cBio Cancer Genomics Portal (http://cbioportal.org), an open-access resource for interactive exploration of multidimensional cancer genomics data sets from more than 5,000 tumor samples from 20 cancer studies [14]. We surveyed the percentage of copy number alternations of BCL2, BCL2L1 and MCL1 among a majority of these tumor samples (Fig. 1a) and found that colorectal cancer has the highest percentage of BCL2L1 gain/amplification among all cancer types. Out of 212 samples, 15 % have BCL2L1 amplification, while MCL1 amplification is found in only 1 %. BCL2 amplifications were not observed, although homozygous deletion is observed in 1 % of colorectal cancer samples (data not shown). Furthermore, there is a good correlation between BCL2L1 copy number gain/amplification and gene expression as determined by RNAseq and microarray analysis (Fig. 1b and data not shown). Cervical cancer also has a high percentage of BCL2L1 gains/amplifications (Fig. 1a) although the sample numbers are limited. Consistent with other studies, we found that DLBCL has the highest percentage of BCL2 amplification (11 %) and lung adenocarcinoma has the highest percentage of MCL1 amplification (20 %) (Fig. 1a). These data indicated that each tumor type has a selective dependency on a particular anti-apoptotic protein for survival and colorectal and cervical tumors are potentially more dependent on BCL-XL for survival.Fig. 1


Genomic analysis and selective small molecule inhibition identifies BCL-X(L) as a critical survival factor in a subset of colorectal cancer.

Zhang H, Xue J, Hessler P, Tahir SK, Chen J, Jin S, Souers AJ, Leverson JD, Lam LT - Mol. Cancer (2015)

Cross-cancer tumor sample analysis identified colorectal cancer as having the highest frequency of BCL2L1 amplification. a Cross-cancer alteration summary for BCL2, BCL2L1 and MCL1 based on data obtained from cBioPortal for Cancer Genomics. b Correlation between gene expression and copy number alteration of BCL2L1 in 212 colorectal cancer samples
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4487849&req=5

Fig1: Cross-cancer tumor sample analysis identified colorectal cancer as having the highest frequency of BCL2L1 amplification. a Cross-cancer alteration summary for BCL2, BCL2L1 and MCL1 based on data obtained from cBioPortal for Cancer Genomics. b Correlation between gene expression and copy number alteration of BCL2L1 in 212 colorectal cancer samples
Mentions: BCL-XL has been implicated as a key survival factor in numerous solid tumors. Since cancer types with BCL2 and MCL1 amplification are more prone to inhibition of these proteins, we reasoned that significant frequency of BCL2L1 amplification in a particular cancer type may indicate dependency on BCL-XL for survival. To identify cancer types with a significant amplification of BCL2L1, we utilized The cBio Cancer Genomics Portal (http://cbioportal.org), an open-access resource for interactive exploration of multidimensional cancer genomics data sets from more than 5,000 tumor samples from 20 cancer studies [14]. We surveyed the percentage of copy number alternations of BCL2, BCL2L1 and MCL1 among a majority of these tumor samples (Fig. 1a) and found that colorectal cancer has the highest percentage of BCL2L1 gain/amplification among all cancer types. Out of 212 samples, 15 % have BCL2L1 amplification, while MCL1 amplification is found in only 1 %. BCL2 amplifications were not observed, although homozygous deletion is observed in 1 % of colorectal cancer samples (data not shown). Furthermore, there is a good correlation between BCL2L1 copy number gain/amplification and gene expression as determined by RNAseq and microarray analysis (Fig. 1b and data not shown). Cervical cancer also has a high percentage of BCL2L1 gains/amplifications (Fig. 1a) although the sample numbers are limited. Consistent with other studies, we found that DLBCL has the highest percentage of BCL2 amplification (11 %) and lung adenocarcinoma has the highest percentage of MCL1 amplification (20 %) (Fig. 1a). These data indicated that each tumor type has a selective dependency on a particular anti-apoptotic protein for survival and colorectal and cervical tumors are potentially more dependent on BCL-XL for survival.Fig. 1

Bottom Line: 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.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.This work demonstrates the utility of characterizing frequent genomic alterations to identify cancer survival genes.

View Article: PubMed Central - PubMed

Affiliation: Oncology Research, AbbVie, 1 N Waukegan Road, North Chicago, IL, 60064-6101, USA. Haichao.zhang@abbvie.com.

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.

No MeSH data available.


Related in: MedlinePlus