Abstract 314: Cell cycle phase-specific drug resistance as an escape mechanism of melanoma cells

Abstract

Abstract The tumor microenvironment is characterized by cancer cell subpopulations with heterogeneous cell cycle profiles. For example, hypoxic areas within tumors contain clusters of cancer cells that arrest in the G1 cell cycle phase. It is conceivable that cancer cells exhibit differential drug sensitivity based on their residence in specific cell cycle phases. Here, we have used two-dimensional and organotypic melanoma culture models in combination with fluorescent cell cycle indicators to investigate the effects of G1-arrest on clinically used melanoma drugs. We demonstrate that G1-arrested melanoma cells, irrespective of the underlying cause mediating G1-arrest, are resistant to induced cell death by the proteasome inhibitor bortezomib and the alkylating agent temozolomide. In contrast, G1-arrested cells were more sensitive to MAPK pathway inhibition. Of clinical relevance, pre-treatment of melanoma cells with a MAPK pathway inhibitor resulted in resistance to temozolomide or bortezomib, while in contrast pre-treatment with temozolomide did not result in resistance to the MAPK pathway inhibitor. In summary, we have 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. Citation Format: Kimberley A. Beaumont, David S. Hill, Sheena M. Daignault, Danae M. Sharp, Brian Gabrielli, Wolfgang Weninger, Nikolas K. Haass. Cell cycle phase-specific drug resistance as an escape mechanism of melanoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 314.