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Low expression of pro-apoptotic proteins Bax, Bak and Smac indicates prolonged progression-free survival in chemotherapy-treated metastatic melanoma.

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posted on 11.01.2021, 17:00 by Cristiano Guttà, Arman Rahman, Claudia Aura, Peter Dynoodt, Emilie M Charles, Elodie Hirschenhahn, Jesuchristopher Joseph, Jasper Wouters, Ciaran de Chaumont, Marian Rafferty, Madhuri Warren, Joost J van den Oord, William M Gallagher, Markus RehmMarkus Rehm
Despite the introduction of novel targeted therapies, chemotherapy still remains the primary treatment for metastatic melanoma in poorly funded healthcare environments or in case of disease relapse, with no reliable molecular markers for progression-free survival (PFS) available. As chemotherapy primarily eliminates cancer cells by apoptosis, we here evaluated if the expression of key apoptosis regulators (Bax, Bak, Bcl-2, Bcl-xL, Smac, Procaspase-9, Apaf-1, Procaspase-3 and XIAP) allows prognosticating PFS in stage III/IV melanoma patients. Following antibody validation, marker expression was determined by automated and manual scoring of immunohistochemically stained tissue microarrays (TMAs) constructed from treatment-naive metastatic melanoma biopsies. Interestingly and counter-intuitively, low expression of the pro-apoptotic proteins Bax, Bak and Smac indicated better prognosis (log-rank p < 0.0001, p = 0.0301 and p = 0.0227 for automated and p = 0.0422, p = 0.0410 and p = 0.0073 for manual scoring). These findings were independently validated in the cancer genome atlas (TCGA) metastatic melanoma cohort (TCGA-SKCM) at transcript level (log-rank p = 0.0004, p = 0.0104 and p = 0.0377). Taking expression heterogeneity between the markers in individual tumour samples into account allowed defining combinatorial Bax, Bak, Smac signatures that were associated with significantly increased PFS (p = 0.0002 and p = 0.0028 at protein and transcript level, respectively). Furthermore, combined low expression of Bax, Bak and Smac allowed predicting prolonged PFS (> 12 months) on a case-by-case basis (area under the receiver operating characteristic curve (ROC AUC) = 0.79). Taken together, our results therefore suggest that Bax, Bak and Smac jointly define a signature with potential clinical utility in chemotherapy-treated metastatic melanoma.

Funding

European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement #642295 (MEL-PLEX)

European Union’s FP7 Marie Sklodowska-Curie Industry-Academia Partnership and Pathways research programme under the grant agreement #611107 (SYS-MEL).

Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy - EXC 2075 – 390740016.

German Research Foundation (FOR2036 (MO 3226/1–1))

Kom op tegen Kanker (Stand up to Cancer), the Flemish Cancer Society

Health Research Board Ireland (HRA POR 2015 1091).

Stichting tegen Kanker (Foundation against Cancer), the Belgian Cancer Society.

History

Associated research data files

Supplementary material at https://doi.org/10.1038/s41419-020-2309-3

Comments

The original article is available at https://www.nature.com/

Published Citation

Guttà C, Rahman A, Aura C, Dynoodt P, Charles EM, Hirschenhahn E, Joseph J, Wouters J, de Chaumont C, Rafferty M, Warren M, van den Oord JJ, Gallagher WM, Rehm M. Low expression of pro-apoptotic proteins Bax, Bak and Smac indicates prolonged progression-free survival in chemotherapy-treated metastatic melanoma. Cell Death & Disease. 2020;11(2):124.

Publication Date

13 February 2020

PubMed ID

13 February 2020

Department/Unit

  • Centre for Systems Medicine
  • Physiology and Medical Physics

Research Area

  • Cancer

Publisher

Springer Nature

Version

  • Published Version (Version of Record)