1. p53 Reactivation by PRIMA-1Met (APR-246) sensitises V600E/KBRAF melanoma to vemurafenib
- Author
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Mohammad Krayem, Catherine Sibille, Ghanem Elias Ghanem, Ahmad Awada, Murielle Wiedig, Ahmad Najem, Renato Morandini, Fabrice Journe, Jean-Christophe Marine, François Sales, and Léon C van Kempen
- Subjects
Male ,0301 basic medicine ,MAPK/ERK pathway ,Quinuclidines ,Cancer Research ,Indoles ,Skin Neoplasms ,Time Factors ,Nude ,Drug Resistance ,Apoptosis ,Cell Proliferation/drug effects ,Mice ,0302 clinical medicine ,Signal Transduction/drug effects ,Skin Neoplasms/drug therapy ,Antineoplastic Combined Chemotherapy Protocols ,Proto-Oncogene Proteins c-akt/metabolism ,Melanoma/drug therapy ,Molecular Targeted Therapy ,Vemurafenib ,Proto-Oncogene Proteins B-raf/antagonists & inhibitors ,Melanoma ,Sulfonamides ,Tumor ,Indoles/pharmacology ,Drug Synergism ,Oncology ,030220 oncology & carcinogenesis ,Tumor Suppressor Protein p53/genetics ,Drug ,Phosphatidylinositol 3-Kinase/metabolism ,Signal Transduction ,medicine.drug ,Proto-Oncogene Proteins B-raf ,Sulfonamides/pharmacology ,Mice, Nude ,Antineoplastic Combined Chemotherapy Protocols/pharmacology ,Cell Line ,Dose-Response Relationship ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Protein Kinase Inhibitors ,neoplasms ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Dose-Response Relationship, Drug ,business.industry ,Apoptosis/drug effects ,Quinuclidines/pharmacology ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Drug Resistance, Neoplasm ,Protein Kinase Inhibitors/pharmacology ,Mutation ,Cutaneous melanoma ,Immunology ,Cancer research ,Neoplasm ,Phosphatidylinositol 3-Kinase ,Tumor Suppressor Protein p53 ,business ,Proto-Oncogene Proteins c-akt ,V600E - 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.
- Published
- 2016