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BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition

Haq, Rizwan ; Yokoyama, Satoru ; Hawryluk, Elena B. ; Jönsson, Göran B LU ; Frederick, Dennie Tampers ; McHenry, Kevin ; Porter, Dale ; Tran, Thanh-Nga ; Love, Kevin T. and Langer, Robert , et al. (2013) In Proceedings of the National Academy of Sciences 110(11). p.4321-4326
Abstract
Although targeting oncogenic mutations in the BRAF serine/threonine kinase with small molecule inhibitors can lead to significant clinical responses in melanoma, it fails to eradicate tumors in nearly all patients. Successful therapy will be aided by identification of intrinsic mechanisms that protect tumor cells from death. Here, we used a bioinformatics approach to identify drug-able, "driver" oncogenes restricted to tumor versus normal tissues. Applying this method to 88 short-term melanoma cell cultures, we show that the antiapoptotic BCL2 family member BCL2A1 is recurrently amplified in similar to 30% of melanomas and is necessary for melanoma growth. BCL2A1 overexpression also promotes melanomagenesis of BRAF-immortalized... (More)
Although targeting oncogenic mutations in the BRAF serine/threonine kinase with small molecule inhibitors can lead to significant clinical responses in melanoma, it fails to eradicate tumors in nearly all patients. Successful therapy will be aided by identification of intrinsic mechanisms that protect tumor cells from death. Here, we used a bioinformatics approach to identify drug-able, "driver" oncogenes restricted to tumor versus normal tissues. Applying this method to 88 short-term melanoma cell cultures, we show that the antiapoptotic BCL2 family member BCL2A1 is recurrently amplified in similar to 30% of melanomas and is necessary for melanoma growth. BCL2A1 overexpression also promotes melanomagenesis of BRAF-immortalized melanocytes. We find that high-level expression of BCL2A1 is restricted to melanoma due to direct transcriptional control by the melanoma oncogene MITF. Although BRAF inhibitors lead to cell cycle arrest and modest apoptosis, we find that apoptosis is significantly enhanced by suppression of BCL2A1 in melanomas with BCL2A1 or MITF amplification. Moreover, we find that BCL2A1 expression is associated with poorer clinical responses to BRAF pathway inhibitors in melanoma patients. Cotreatment of melanomas with BRAF inhibitors and obatoclax, an inhibitor of BCL2A1 and other BCL2 family members, overcomes intrinsic resistance to BRAF inhibitors in BCL2A1-amplified cells in vitro and in vivo. These studies identify MITF-BCL2A1 as a lineage-specific oncogenic pathway in melanoma and underscore its role for improved response to BRAF-directed therapy. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences
volume
110
issue
11
pages
4321 - 4326
publisher
National Acad Sciences
external identifiers
  • wos:000316238300040
  • scopus:84875019584
  • pmid:23447565
ISSN
1091-6490
DOI
10.1073/pnas.1205575110
language
English
LU publication?
yes
id
67f8ae65-7b36-4bf4-b007-1cabdb2406bf (old id 3760944)
date added to LUP
2016-04-01 10:38:38
date last changed
2020-09-09 01:31:34
@article{67f8ae65-7b36-4bf4-b007-1cabdb2406bf,
  abstract     = {Although targeting oncogenic mutations in the BRAF serine/threonine kinase with small molecule inhibitors can lead to significant clinical responses in melanoma, it fails to eradicate tumors in nearly all patients. Successful therapy will be aided by identification of intrinsic mechanisms that protect tumor cells from death. Here, we used a bioinformatics approach to identify drug-able, "driver" oncogenes restricted to tumor versus normal tissues. Applying this method to 88 short-term melanoma cell cultures, we show that the antiapoptotic BCL2 family member BCL2A1 is recurrently amplified in similar to 30% of melanomas and is necessary for melanoma growth. BCL2A1 overexpression also promotes melanomagenesis of BRAF-immortalized melanocytes. We find that high-level expression of BCL2A1 is restricted to melanoma due to direct transcriptional control by the melanoma oncogene MITF. Although BRAF inhibitors lead to cell cycle arrest and modest apoptosis, we find that apoptosis is significantly enhanced by suppression of BCL2A1 in melanomas with BCL2A1 or MITF amplification. Moreover, we find that BCL2A1 expression is associated with poorer clinical responses to BRAF pathway inhibitors in melanoma patients. Cotreatment of melanomas with BRAF inhibitors and obatoclax, an inhibitor of BCL2A1 and other BCL2 family members, overcomes intrinsic resistance to BRAF inhibitors in BCL2A1-amplified cells in vitro and in vivo. These studies identify MITF-BCL2A1 as a lineage-specific oncogenic pathway in melanoma and underscore its role for improved response to BRAF-directed therapy.},
  author       = {Haq, Rizwan and Yokoyama, Satoru and Hawryluk, Elena B. and Jönsson, Göran B and Frederick, Dennie Tampers and McHenry, Kevin and Porter, Dale and Tran, Thanh-Nga and Love, Kevin T. and Langer, Robert and Anderson, Daniel G. and Garraway, Levi A. and Duncan, Lyn McDivitt and Morton, Donald L. and Hoon, Dave S. B. and Wargo, Jennifer A. and Song, Jun S. and Fisher, David E.},
  issn         = {1091-6490},
  language     = {eng},
  number       = {11},
  pages        = {4321--4326},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition},
  url          = {http://dx.doi.org/10.1073/pnas.1205575110},
  doi          = {10.1073/pnas.1205575110},
  volume       = {110},
  year         = {2013},
}