PMID- 25529535 OWN - NLM STAT- MEDLINE DCOM- 20150421 LR - 20201222 IS - 1873-2968 (Electronic) IS - 0006-2952 (Linking) VI - 93 IP - 3 DP - 2015 Feb 1 TI - Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in Vemurafenib-resistant melanoma cells. PG - 290-304 LID - S0006-2952(14)00699-6 [pii] LID - 10.1016/j.bcp.2014.12.003 [doi] AB - Vemurafenib (PLX4032), an inhibitor of BRAF(V600E), has demonstrated significant clinical anti-melanoma effects. However, the majority of treated patients develop resistance, due to a variety of molecular mechanisms including MAPK reactivation through MEK. The induction of a cancer cell death modality associated with danger-signalling resulting in surface mobilization of crucial damage-associated-molecular-patterns (DAMPs), e.g. calreticulin (CRT) and heat shock protein-90 (HSP90), from dying cells, is emerging to be crucial for therapeutic success. Both cell death and danger-signalling are modulated by autophagy, a key adaptation mechanism stimulated during melanoma progression. However, whether melanoma cell death induced by MAPK inhibition is associated with danger-signalling, and the reliance of these mechanisms on autophagy, has not yet been scrutinized. Using a panel of isogenic PLX4032-sensitive and resistant melanoma cell lines we show that PLX4032-induced caspase-dependent cell death and DAMPs exposure in the drug-sensitive cells, but failed to do so in the drug-resistant cells, displaying heightened MEK activation. MEK inhibitor, U0126, treatment sensitized PLX4032-resistant cells to death and re-established their danger-signalling capacity. Only melanoma cells exposing death-induced danger-signals were phagocytosed and induced DC maturation. Although the PLX4032-resistant melanoma cells displayed higher basal and drug-induced autophagy, compromising autophagy, pharmacologically or by ATG5 knockdown, was insufficient to re-establish their PLX4032 sensitivity. Interestingly, autophagy abrogation was particularly efficacious in boosting cell death and ecto-CRT/ecto-HSP90 in PLX4032-resistant cells upon blockage of MEK hyper-activation by U0126. Thus combination of MEK inhibitors with autophagy blockers may represent a novel treatment regime to increase both cell death and danger-signalling in Vemurafenib-resistant metastatic melanoma. CI - Copyright (c) 2015 Elsevier Inc. All rights reserved. FAU - Martin, S AU - Martin S AD - Cell Death Research and Therapy Unit, Department for Cellular and Molecular Medicine, University of Leuven (KU Leuven), Campus Gasthuisberg, O&N1, Herestraat 49, Box 802, 3000 Leuven, Belgium. FAU - Dudek-Peric, A M AU - Dudek-Peric AM AD - Cell Death Research and Therapy Unit, Department for Cellular and Molecular Medicine, University of Leuven (KU Leuven), Campus Gasthuisberg, O&N1, Herestraat 49, Box 802, 3000 Leuven, Belgium. FAU - Maes, H AU - Maes H AD - Cell Death Research and Therapy Unit, Department for Cellular and Molecular Medicine, University of Leuven (KU Leuven), Campus Gasthuisberg, O&N1, Herestraat 49, Box 802, 3000 Leuven, Belgium. FAU - Garg, A D AU - Garg AD AD - Cell Death Research and Therapy Unit, Department for Cellular and Molecular Medicine, University of Leuven (KU Leuven), Campus Gasthuisberg, O&N1, Herestraat 49, Box 802, 3000 Leuven, Belgium. FAU - Gabrysiak, M AU - Gabrysiak M AD - Cell Death Research and Therapy Unit, Department for Cellular and Molecular Medicine, University of Leuven (KU Leuven), Campus Gasthuisberg, O&N1, Herestraat 49, Box 802, 3000 Leuven, Belgium. FAU - Demirsoy, S AU - Demirsoy S AD - Cell Death Research and Therapy Unit, Department for Cellular and Molecular Medicine, University of Leuven (KU Leuven), Campus Gasthuisberg, O&N1, Herestraat 49, Box 802, 3000 Leuven, Belgium. FAU - Swinnen, J V AU - Swinnen JV AD - Laboratory of Lipid Metabolism and Cancer, Department of Oncology, University of Leuven (KU Leuven), Campus Gasthuisberg, O&N1, Herestraat 49, Box 818, 3000 Leuven, Belgium. FAU - Agostinis, P AU - Agostinis P AD - Cell Death Research and Therapy Unit, Department for Cellular and Molecular Medicine, University of Leuven (KU Leuven), Campus Gasthuisberg, O&N1, Herestraat 49, Box 802, 3000 Leuven, Belgium. Electronic address: patrizia.agostinis@med.kuleuven.be. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20141218 PL - England TA - Biochem Pharmacol JT - Biochemical pharmacology JID - 0101032 RN - 0 (Butadienes) RN - 0 (Enzyme Inhibitors) RN - 0 (Indoles) RN - 0 (Nitriles) RN - 0 (Sulfonamides) RN - 0 (U 0126) RN - 207SMY3FQT (Vemurafenib) RN - EC 2.7.11.25 (MAP Kinase Kinase Kinases) SB - IM EIN - Biochem Pharmacol. 2020 May;175:113810. PMID: 32085947 MH - Autophagy/*drug effects/physiology MH - Butadienes/pharmacology MH - Cell Death/drug effects/physiology MH - Coculture Techniques MH - Drug Resistance, Neoplasm/*drug effects/physiology MH - Enzyme Inhibitors/pharmacology MH - Humans MH - Indoles/*pharmacology/therapeutic use MH - MAP Kinase Kinase Kinases/*antagonists & inhibitors/metabolism MH - *Melanoma/drug therapy/metabolism MH - Nitriles/pharmacology MH - Signal Transduction/*drug effects/physiology MH - Sulfonamides/*pharmacology/therapeutic use MH - Vemurafenib OTO - NOTNLM OT - Autophagy OT - Cell death OT - Danger-signalling OT - Melanoma OT - PLX4032 EDAT- 2014/12/23 06:00 MHDA- 2015/04/22 06:00 CRDT- 2014/12/23 06:00 PHST- 2014/11/05 00:00 [received] PHST- 2014/12/08 00:00 [revised] PHST- 2014/12/08 00:00 [accepted] PHST- 2014/12/23 06:00 [entrez] PHST- 2014/12/23 06:00 [pubmed] PHST- 2015/04/22 06:00 [medline] AID - S0006-2952(14)00699-6 [pii] AID - 10.1016/j.bcp.2014.12.003 [doi] PST - ppublish SO - Biochem Pharmacol. 2015 Feb 1;93(3):290-304. doi: 10.1016/j.bcp.2014.12.003. Epub 2014 Dec 18.