Stromal cell effects on melanoma cell drug response

Abstract

Objective: Melanoma is currently one of the deadliest forms of skin disease in the United States. However in the past decade there have been significant advances in treatment. Among the most promising recent developments, inhibitors of the serine/threonine-protein kinase B-Raf (BRAF inhibitors) such as vemurafenib show great promise and have been shown to increase the median survival of patients with melanoma cells that harbor a mutation of the BRAF gene. While BRAF inhibitors and other treatment therapies have much potential, more needs to be done to improve treatment. As with other cancers, a major hurdle in the treatment of melanoma is the eventual tumor resistance to drug therapy. Accessory cells are thought to play a large role in mediating tumor resistance to drug treatment. Stromal cells have been known to release cytokines and growth factors that aid in cancer proliferation. They can also expression adhesion molecules that further help to aid cell growth and tumor development. It has also been demonstrated that these accessory cells can significantly alter cancer cell drug response as a result of the factors they release or express on their surface. In this study we hypothesize that certain anti-cancer drugs will behave differently against melanoma cell line A375 in the presence versus the absence of stromal cells. Methods: Melanoma cell line A375 was grown on 384 well plates in the presence or absence of different stromal cell lines. A number of different drugs were screened using Compartment-Specific Bioluminescence Imaging to determine if there was a difference in A375 proliferation after drug treatment in the presence versus absence of accessory cells. After an initial screen, a few drugs were chosen to generate dose-response curves to determine if different drugs had different effects at various doses in the presence or absence of stromal cells. [TRUNCATED]