p53 Reactivation by PRIMA-1(Met) (APR-246) sensitises (V600E/K)BRAF melanoma to vemurafenib
Authors: Ahmad Awada
Mohammad Krayem
Renato Morandini
Ghanem Ghanem
Fabrice Journe
François Salès
Ahmad Najem
Jean-Christophe Marine
Leon C van Kempen
Murielle Wiedig
Catherine Sibille
Journal: European Journal of Cancer (2016)
Discipline: CLINICAL MEDICINE
Keywords: (V600E/K)BRAF; Drug resistance; Melanoma; PRIMA-1(Met); Vemurafenib
Affiliations: Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium., Department of Pathology, McGill University and Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Côte-Sainte-Catherine, H3T 1E2 Montreal, QC, Canada., Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium., Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium., Laboratory for Molecular Cancer Biology, Center for Human Genetics, KUleuven, Leuven, Belgium; Laboratory for Molecular Cancer Biology, Center for the Biology of Disease, VIB-KULeuven, Belgium., Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: .

Abstract:  Intrinsic and acquired resistance of metastatic melanoma to (V600E/K)BRAF and/or MEK inhibitors, which is often caused by activation of the PI3K/AKT survival pathway, represents a major clinical challenge. Given that p53 is capable of antagonising PI3K/AKT activation we hypothesised that pharmacological restoration of p53 activity may increase the sensitivity of BRAF-mutant melanoma to MAPK-targeted therapy and eventually delay and/or prevent acquisition of drug resistance. To test this possibility we exposed a panel of vemurafenib-sensitive and resistant (innate and acquired) (V600E/K)BRAF melanomas to a (V600E/K)BRAF inhibitor (vemurafenib) alone or in combination with a direct p53 activator (PRIMA-1(Met)/APR-246). Strikingly, PRIMA-1(Met) synergised with vemurafenib to induce apoptosis and suppress proliferation of (V600E/K)BRAF melanoma cells in vitro and to inhibit tumour growth in vivo. Importantly, this drug combination decreased the viability of both vemurafenib-sensitive and resistant melanoma cells irrespectively of the TP53 status. Notably, p53 reactivation was invariably accompanied by PI3K/AKT pathway inhibition, the activity of which was found as a dominant resistance mechanism to BRAF inhibition in our lines. From all various combinatorial modalities tested, targeting the MAPK and PI3K signalling pathways through p53 reactivation or not, the PRIMA-1(Met)/vemurafenib combination was the most cytotoxic. We conclude that PRIMA-1(Met) through its ability to directly reactivate p53 regardless of the mechanism causing its deactivation, and thereby dampen PI3K signalling, sensitises (V600E/K)BRAF-positive melanoma to BRAF inhibitors. 

Retracted: No

PubPeer comments:
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 We thank the referee for the interest in our work and pointing this out. This is indeed the result of an unintentional mistake, which occured when mounting the final figure. Note that 5 different WB under the same experimental conditions (biological replicates) have been produced and the same results were obtained (see for instance the Figure below). Note that this mistakes does not change or alter the content and conclusions of our paper. Many authors have already documented that inhibiting mutBRAF does not affect ERK expression, while decreasing pERK levels. The mistake indeed concerns a control experiments, which have and can reproduced very easily. We sincerely apologize for this mistake (and will submit an erratum to the journal in which this work was published). ![file] , 
 In addition to the original concern (for which I did not find a correction), Figure 4A (left) and Figure 5B (right) appear to have a duplicated band, although they seem to be described differently. Could the unnamed author of #2 please provide the original uncropped scans? *** ![file] , 
 It also appears that a portion of a band in Figure 4A (top) and Figure 5E (bottom) are the same, after flipping horizontally. Again, it would be appreciated if the authors could provide the original uncropped scans. *** ![file] , 
 ERRATUM https: www.sciencedirect.com science article pii S0959804922005275?via%3Dihub ,