Am J Cancer Res 2012;2(6):726-735
Original Article
Downregulation of Noxa by RAF/MEK inhibition
counteracts cell death response in mutant
B-RAF melanoma cells
Kevin J Basile, Andrew E Aplin
Department of Cancer Biology and Kimmel Cancer Center; Department of Dermatology and Cutaneous Biology,
Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA
Received October 28, 2012; Accepted November 16, 2012; Epub November 20, 2012; Published November 30, 2012
Abstract: FDA approval of new therapies in 2011 has greatly expanded the treatment options for metastatic melanoma.
Patients with V600 mutant v-raf murine sarcoma viral oncogene homolog B1 (B-RAF) positive metastatic
melanoma are now treated with the RAF inhibitor, vemurafenib (Zelboraf) as a first line therapy. Vemurafenib decreases
tumor size by at least 30% in approximately 50% of patients and increases progression-free survival and
overall patient survival compared to the previous standard-of-care, dacarbazine. However, some patients treated
with vemurafenib fail to show significant tumor shrinkage, and most patients who initially respond to the drug eventually
show disease progression. Therefore, there is a clinical need to improve efficacy and prevent resistance to vemurafenib.
It has been previously shown that cell death resulting from RAF/mitogen-activated protein kinase kinase
(MEK) inhibition is largely dependent on increased expression of pro-apoptotic, Bcl-2 homology domain (BH3)-only
proteins, such as Bcl-2-like 11 (Bim-EL) and Bcl-2 modifying factor (Bmf). Here, we show that contrary to expression
of Bim-EL and Bmf, the pro-apoptotic, BH3-only protein, phorbol-12-myristate-13-acetate-induced protein 1 (Noxa),
is strongly downregulated after RAF/MEK inhibition. This downregulation occurs at both the protein and mRNA
level of expression and is associated with the inhibition of cell cycle progression. Restoring expression of Noxa in
combination with RAF/MEK inhibition enhances cell death. Co-expression of the pro-survival, B-cell CLL/lymphoma
2 (Bcl-2) family member, myeloid cell leukemia sequence 1 (Mcl-1), with Noxa fully mitigates the enhanced cell
death associated with increased Noxa expression. These data indicate that manipulating the Noxa/Mcl-1 axis may
enhance the efficacy of RAF/MEK inhibitors. (ajcr0000157).
Keywords: Melanoma, B-RAF, Noxa, RAF/MEK inhibition
Address all correspondence to:
Dr. Andrew E Aplin
Department of Cancer Biology and Kimmel Cancer Center
Thomas Jefferson University
233 South 10th Street, Philadelphia, PA 19107, USA.
Tel: (215) 503-7296; Fax: (215) 923-9248
E-mail: andrew.aplin@kimmelcancercenter.org
Original Article
Downregulation of Noxa by RAF/MEK inhibition
counteracts cell death response in mutant
B-RAF melanoma cells
Kevin J Basile, Andrew E Aplin
Department of Cancer Biology and Kimmel Cancer Center; Department of Dermatology and Cutaneous Biology,
Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA
Received October 28, 2012; Accepted November 16, 2012; Epub November 20, 2012; Published November 30, 2012
Abstract: FDA approval of new therapies in 2011 has greatly expanded the treatment options for metastatic melanoma.
Patients with V600 mutant v-raf murine sarcoma viral oncogene homolog B1 (B-RAF) positive metastatic
melanoma are now treated with the RAF inhibitor, vemurafenib (Zelboraf) as a first line therapy. Vemurafenib decreases
tumor size by at least 30% in approximately 50% of patients and increases progression-free survival and
overall patient survival compared to the previous standard-of-care, dacarbazine. However, some patients treated
with vemurafenib fail to show significant tumor shrinkage, and most patients who initially respond to the drug eventually
show disease progression. Therefore, there is a clinical need to improve efficacy and prevent resistance to vemurafenib.
It has been previously shown that cell death resulting from RAF/mitogen-activated protein kinase kinase
(MEK) inhibition is largely dependent on increased expression of pro-apoptotic, Bcl-2 homology domain (BH3)-only
proteins, such as Bcl-2-like 11 (Bim-EL) and Bcl-2 modifying factor (Bmf). Here, we show that contrary to expression
of Bim-EL and Bmf, the pro-apoptotic, BH3-only protein, phorbol-12-myristate-13-acetate-induced protein 1 (Noxa),
is strongly downregulated after RAF/MEK inhibition. This downregulation occurs at both the protein and mRNA
level of expression and is associated with the inhibition of cell cycle progression. Restoring expression of Noxa in
combination with RAF/MEK inhibition enhances cell death. Co-expression of the pro-survival, B-cell CLL/lymphoma
2 (Bcl-2) family member, myeloid cell leukemia sequence 1 (Mcl-1), with Noxa fully mitigates the enhanced cell
death associated with increased Noxa expression. These data indicate that manipulating the Noxa/Mcl-1 axis may
enhance the efficacy of RAF/MEK inhibitors. (ajcr0000157).
Keywords: Melanoma, B-RAF, Noxa, RAF/MEK inhibition
Address all correspondence to:
Dr. Andrew E Aplin
Department of Cancer Biology and Kimmel Cancer Center
Thomas Jefferson University
233 South 10th Street, Philadelphia, PA 19107, USA.
Tel: (215) 503-7296; Fax: (215) 923-9248
E-mail: andrew.aplin@kimmelcancercenter.org
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American Journal of Cancer Research
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