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

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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; Frederick, Dennie Tampers; McHenry, Kevin; Porter, Dale; Tran, Thanh-Nga; Love, Kevin T.; Langer, Robert; Anderson, Daniel G.; Garraway, Levi A.; Duncan, Lyn McDivitt; Morton, Donald L.; Hoon, Dave S. B.; Wargo, Jennifer A.; Song, Jun S.; Fisher, David E.

I: Proceedings of the National Academy of Sciences, Vol. 110, Nr. 11, 2013, s. 4321-4326.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Haq, R, Yokoyama, S, Hawryluk, EB, Jönsson, GB, Frederick, DT, McHenry, K, Porter, D, Tran, T-N, Love, KT, Langer, R, Anderson, DG, Garraway, LA, Duncan, LM, Morton, DL, Hoon, DSB, Wargo, JA, Song, JS & Fisher, DE 2013, 'BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition', Proceedings of the National Academy of Sciences, vol. 110, nr. 11, s. 4321-4326. https://doi.org/10.1073/pnas.1205575110

APA

CBE

Haq R, Yokoyama S, Hawryluk EB, Jönsson GB, Frederick DT, McHenry K, Porter D, Tran T-N, Love KT, Langer R, Anderson DG, Garraway LA, Duncan LM, Morton DL, Hoon DSB, Wargo JA, Song JS, Fisher DE. 2013. BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition. Proceedings of the National Academy of Sciences. 110(11):4321-4326. https://doi.org/10.1073/pnas.1205575110

MLA

Vancouver

Author

Haq, Rizwan ; Yokoyama, Satoru ; Hawryluk, Elena B. ; Jönsson, Göran B ; Frederick, Dennie Tampers ; McHenry, Kevin ; Porter, Dale ; Tran, Thanh-Nga ; Love, Kevin T. ; Langer, Robert ; Anderson, Daniel G. ; Garraway, Levi A. ; Duncan, Lyn McDivitt ; Morton, Donald L. ; Hoon, Dave S. B. ; Wargo, Jennifer A. ; Song, Jun S. ; Fisher, David E. / BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition. I: Proceedings of the National Academy of Sciences. 2013 ; Vol. 110, Nr. 11. s. 4321-4326.

RIS

TY - JOUR

T1 - BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition

AU - Haq, Rizwan

AU - Yokoyama, Satoru

AU - Hawryluk, Elena B.

AU - Jönsson, Göran B

AU - Frederick, Dennie Tampers

AU - McHenry, Kevin

AU - Porter, Dale

AU - Tran, Thanh-Nga

AU - Love, Kevin T.

AU - Langer, Robert

AU - Anderson, Daniel G.

AU - Garraway, Levi A.

AU - Duncan, Lyn McDivitt

AU - Morton, Donald L.

AU - Hoon, Dave S. B.

AU - Wargo, Jennifer A.

AU - Song, Jun S.

AU - Fisher, David E.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1205575110

DO - 10.1073/pnas.1205575110

M3 - Article

VL - 110

SP - 4321

EP - 4326

JO - Proceedings of the National Academy of Sciences

T2 - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 1091-6490

IS - 11

ER -