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
N1 - Copyright © 2015 Elsevier Ltd. All rights reserved.
PY - 2016
Y1 - 2016
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.
AB - 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.
KW - Animals
KW - Antineoplastic Combined Chemotherapy Protocols/pharmacology
KW - Apoptosis/drug effects
KW - Cell Line, Tumor
KW - Cell Proliferation/drug effects
KW - Dose-Response Relationship, Drug
KW - Drug Resistance, Neoplasm
KW - Drug Synergism
KW - Genetic Predisposition to Disease
KW - Humans
KW - Indoles/pharmacology
KW - Male
KW - Melanoma/drug therapy
KW - Mice, Nude
KW - Molecular Targeted Therapy
KW - Mutation
KW - Phosphatidylinositol 3-Kinase/metabolism
KW - Protein Kinase Inhibitors/pharmacology
KW - Proto-Oncogene Proteins B-raf/antagonists & inhibitors
KW - Proto-Oncogene Proteins c-akt/metabolism
KW - Quinuclidines/pharmacology
KW - Signal Transduction/drug effects
KW - Skin Neoplasms/drug therapy
KW - Sulfonamides/pharmacology
KW - Time Factors
KW - Tumor Suppressor Protein p53/genetics
KW - Vemurafenib
KW - Xenograft Model Antitumor Assays
U2 - 10.1016/j.ejca.2015.12.002
DO - 10.1016/j.ejca.2015.12.002
M3 - Article
C2 - 26790143
SN - 0959-8049
VL - 55
SP - 98
EP - 110
JO - European Journal of Cancer
JF - European Journal of Cancer
ER -