Abstract B32: Responses of direct in vivo melanoma xenograft cells to targeted therapeutics

The purpose of this study was to investigate the mechanism of resistance of a melanoma cell line generated from a direct in vivo xenograft (DIVX) model. Although BRAF and MKK1/2 inhibitors have produced positive clinical responses in melanoma patients with BRAF-V600 mutations, between 25-50% of patients show intrinsic resistance. Deciphering the mechanisms of intrinsic resistance will be critical for developing future treatment strategies. MB947P cells were established from a direct in vivo xenograft of a resected metastatic melanoma and exhibited innate resistance to apoptosis induced by MKK1/2 inhibitor (AZD6244/selumetinib). In contrast, the established metastatic melanoma cell line, WM239A, showed a strong apoptotic response, induced by inhibitor. Microarray expression profiling was carried out on MB947P and WM239A cells in the presence and absence of drug. The results showed that in MB947P cells inhibitor-dependent induction of Bim was minimal. In contrast, Bim was strongly induced by inhibitor in WM239A cells, where siRNA knockdown of Bim demonstrated its requirement for the apoptotic response. This suggests that the lack of apoptotic response in MB947P cells may be caused by a block in Bim induction through an unknown mechanism. Finally, co-culture of MB947P and WM239A cells showed partial inhibition of the apoptotic response in WM239A cells after AZD6244 treatment. This suggests the potential existence of a soluble factor in MB947P cells that confers resistance to apo...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Principles of Response and Resistance to Therapy Source Type: research