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Inhibition of autophagy enhances the effects of the AKT inhibitor MK-2206 when combined with paclitaxel and carboplatin in BRAF wild-type melanoma.
- Source :
-
Pigment cell & melanoma research [Pigment Cell Melanoma Res] 2014 May; Vol. 27 (3), pp. 465-78. Date of Electronic Publication: 2014 Feb 21. - Publication Year :
- 2014
-
Abstract
- 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.<br /> (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Subjects :
- Aged
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Carboplatin administration & dosage
Clone Cells drug effects
Drug Resistance, Neoplasm drug effects
Drug Synergism
Female
Heterocyclic Compounds, 3-Ring administration & dosage
Humans
Male
Melanoma enzymology
Melanoma pathology
Molecular Targeted Therapy
Neoplasm Proteins antagonists & inhibitors
Neoplasm Proteins genetics
Paclitaxel administration & dosage
Protein Kinase Inhibitors administration & dosage
Proto-Oncogene Proteins B-raf genetics
Reactive Oxygen Species metabolism
Skin Neoplasms enzymology
Skin Neoplasms pathology
Spheroids, Cellular
Tumor Stem Cell Assay
Antineoplastic Combined Chemotherapy Protocols pharmacology
Autophagy drug effects
Heterocyclic Compounds, 3-Ring pharmacology
Melanoma drug therapy
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins c-akt antagonists & inhibitors
Skin Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1755-148X
- Volume :
- 27
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Pigment cell & melanoma research
- Publication Type :
- Academic Journal
- Accession number :
- 24490764
- Full Text :
- https://doi.org/10.1111/pcmr.12227