Cell cycle phase-specific drug resistance as an escape mechanism of melanoma cells

Beaumont, Kimberley A., Hill, David S., Daignault, Sheena M., Lui, Goldie Y. L., Sharp, Danae M., Gabrielli, Brian, Weninger, Wolfgang and Haass, Nikolas K. (2016) Cell cycle phase-specific drug resistance as an escape mechanism of melanoma cells. Journal of Investigative Dermatology, 136 7: 1479-1489. doi:10.1016/j.jid.2016.02.805

Author Beaumont, Kimberley A.
Hill, David S.
Daignault, Sheena M.
Lui, Goldie Y. L.
Sharp, Danae M.
Gabrielli, Brian
Weninger, Wolfgang
Haass, Nikolas K.
Title Cell cycle phase-specific drug resistance as an escape mechanism of melanoma cells
Journal name Journal of Investigative Dermatology   Check publisher's open access policy
ISSN 0022-202X
Publication date 2016-07
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.jid.2016.02.805
Open Access Status Not Open Access
Volume 136
Issue 7
Start page 1479
End page 1489
Total pages 11
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2017
Language eng
Formatted abstract
The tumor microenvironment is characterized by cancer cell subpopulations with heterogeneous cell cycle profiles. For example, hypoxic tumor zones contain clusters of cancer cells that arrest in G1 phase. It is conceivable that neoplastic cells exhibit differential drug sensitivity based on their residence in specific cell cycle phases. In this study, we used two-dimensional and organotypic melanoma culture models in combination with fluorescent cell cycle indicators to investigate the effects of cell cycle phases on clinically used drugs. We demonstrate that G1-arrested melanoma cells, irrespective of the underlying cause mediating G1 arrest, are resistant to apoptosis induced by the proteasome inhibitor bortezomib or the alkylating agent temozolomide. In contrast, G1-arrested cells were more sensitive to mitogen-activated protein kinase pathway inhibitor-induced cell death. Of clinical relevance, pretreatment of melanoma cells with a mitogen-activated protein kinase pathway inhibitor, which induced G1 arrest, resulted in resistance to temozolomide or bortezomib. On the other hand, pretreatment with temozolomide, which induced G2 arrest, did not result in resistance to mitogen-activated protein kinase pathway inhibitors. In summary, we established a model to study the effects of the cell cycle on drug sensitivity. Cell cycle phase-specific drug resistance is an escape mechanism of melanoma cells that has implications on the choice and timing of drug combination therapies.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
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