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p53 Reactivation by PRIMA-1(Met) (APR-246) sensitises (V600E/K)BRAF melanoma to vemurafenib.
Eur J Cancer. 2016 Mar; 55:98-110.EJ

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.

Authors+Show Affiliations

Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.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: gghanem@ulb.ac.be.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26790143

Citation

Krayem, Mohammad, et al. "P53 Reactivation By PRIMA-1(Met) (APR-246) Sensitises (V600E/K)BRAF Melanoma to Vemurafenib." European Journal of Cancer (Oxford, England : 1990), vol. 55, 2016, pp. 98-110.
Krayem M, Journe F, Wiedig M, et al. P53 Reactivation by PRIMA-1(Met) (APR-246) sensitises (V600E/K)BRAF melanoma to vemurafenib. Eur J Cancer. 2016;55:98-110.
Krayem, M., Journe, F., Wiedig, M., Morandini, R., Najem, A., Salès, F., van Kempen, L. C., Sibille, C., Awada, A., Marine, J. C., & Ghanem, G. (2016). P53 Reactivation by PRIMA-1(Met) (APR-246) sensitises (V600E/K)BRAF melanoma to vemurafenib. European Journal of Cancer (Oxford, England : 1990), 55, 98-110. https://doi.org/10.1016/j.ejca.2015.12.002
Krayem M, et al. P53 Reactivation By PRIMA-1(Met) (APR-246) Sensitises (V600E/K)BRAF Melanoma to Vemurafenib. Eur J Cancer. 2016;55:98-110. PubMed PMID: 26790143.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - p53 Reactivation by PRIMA-1(Met) (APR-246) sensitises (V600E/K)BRAF melanoma to vemurafenib. AU - Krayem,Mohammad, AU - Journe,Fabrice, AU - Wiedig,Murielle, AU - Morandini,Renato, AU - Najem,Ahmad, AU - Salès,François, AU - van Kempen,Leon C, AU - Sibille,Catherine, AU - Awada,Ahmad, AU - Marine,Jean-Christophe, AU - Ghanem,Ghanem, Y1 - 2016/01/17/ PY - 2015/12/02/received PY - 2015/12/07/accepted PY - 2016/1/21/entrez PY - 2016/1/21/pubmed PY - 2016/6/30/medline KW - (V600E/K)BRAF KW - Drug resistance KW - Melanoma KW - PRIMA-1(Met) KW - Vemurafenib KW - p53 SP - 98 EP - 110 JF - European journal of cancer (Oxford, England : 1990) JO - Eur. J. Cancer VL - 55 N2 - 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. SN - 1879-0852 UR - https://www.unboundmedicine.com/medline/citation/26790143/p53_Reactivation_by_PRIMA_1_Met___APR_246__sensitises__V600E/K_BRAF_melanoma_to_vemurafenib_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0959-8049(15)01136-3 DB - PRIME DP - Unbound Medicine ER -