p53 Reactivation by PRIMA-1Met (APR-246) sensitisesV600E/K BRAF melanoma to vemurafenib

• Published in: European journal of cancer (1990) 2015, Vol.55, p.98-110
• Main Authors: Krayem, Mohammad, Journe, Fabrice, Wiedig, Murielle, Morandini, Renato, Najem, Ahmad, Salès, François, van Kempen, Leon C, Sibille, Catherine, Awada, Ahmad, Marine, Jean-Christophe, Ghanem, Ghanem
• Format: Article
• Language: English
• Subjects: Hematology, Oncology and Palliative Medicine
• ISSN: 0959-8049
• DOI: 10.1016/j.ejca.2015.12.002

Abstract Intrinsic and acquired resistance of metastatic melanoma toV600E/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 aV600E/K BRAF inhibitor (vemurafenib) alone or in combination with a direct p53 activator (PRIMA-1Met /APR-246). Strikingly, PRIMA-1Met synergised with vemurafenib to induce apoptosis and suppress proliferation ofV600E/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-1Met /vemurafenib combination was the most cytotoxic. We conclude that PRIMA-1Met through its ability to directly reactivate p53 regardless of the mechanism causing its deactivation, and thereby dampen PI3K signalling, sensitisesV600E/K BRAF-positive melanoma to BRAF inhibitors.