Inhibition of autophagy enhances the effects of the AKT inhibitor MK-2206 when combined with paclitaxel and carboplatin in BRAF wild-type melanoma.
This study investigates the mechanism of action behind the long-term responses (12-16 months) of two BRAF WT melanoma patients to the AKT inhibitor MK-2206 in combination with paclitaxel and carboplatin. Although single agent MK-2206 inhibited phospho-AKT signaling, it did not impact in vitro melanoma growth or survival. The combination of MK-2206 with paclitaxel and carboplatin was cytotoxic in long-term colony formation and 3D spheroid assays, and induced autophagy. Autophagy was initially protective with autophagy inhibitors and deletion of ATG5 found to enhance cytotoxicity. Although prolonged autophagy induction (>6 days) led to caspase-dependent apoptosis, drug resistant clones still emerged. Autophagy inhibition enhanced the cell death response through reactive oxygen species and could be reversed by anti-oxidants. We demonstrate for the first time that AKT inhibition in combination with chemotherapy may have clinical activity in BRAF WT melanoma and show that an autophagy inhibitor may prevent resistance to these drugs.
Department of Molecular Oncology, The Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Vito W
VW
Rebecca
Renato R
RR
Massaro
Inna V
IV
Fedorenko
Vernon K
VK
Sondak
Alexander R A
AR
Anderson
Eunjung
E
Kim
Ravi K
RK
Amaravadi
Silvya S
SS
Maria-Engler
Jane L
JL
Messina
Geoffrey T
GT
Gibney
Ragini R
RR
Kudchadkar
Keiran S M
KS
Smalley
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects*; D016190:Carboplatin / Q000008:administration & dosage; D002999:Clone Cells / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D017239:Paclitaxel / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018874:Spheroids, Cellular; D014410:Tumor Stem Cell Assay
D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D016190:Carboplatin; C494918:AKT1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel
AKT; BRAF; apoptosis; autophagy; chemotherapy; melanoma