Adrenocortical carcinoma (ACC) is an aggressive tumor of the adrenal cortex. It affects 1-2 per million and has a 5 year survival rate of 25-30% due to late detection and a lack of effective systemic therapy. Mitotane, an isomer of the insecticide DDT, is the only compound approved for the treatment of patients with ACC. It has a poor response rate (22% as a single agent) and a toxicity profile that often results in dose reduction or cessation of therapy altogether. New therapies are desperately needed.

Expression profiling of ACC by ourselves and others highlights the importance of the G2/M transition, the p53 pathway, and signaling of IGF2 through IGF1R. Using this knowledge, we profiled the in vitro chemosensitivity of the two ACC cell lines, H295R and SW-13, to compounds that target aspects of these pathways. Cells were plated, and drug added 24 hours later in a 3-fold serial dilution, with the exception of mitotane which was done as a 1.5-fold serial dilution. Viability was assessed by CellTiter Glo at 3 different time points. The cell lines show sensitivity to compounds that target the G2/M transition (VX-680 and BI-2536) and EGFR (erlotinib). The difference in response between H295R and SW-13 to LY294002 suggests the cell lines harbor a difference in the relative contributions of PI3K signaling versus Ras-Raf-MEK signaling downstream of IGF1R. Additionally, the response of both cell lines to erlotinib suggests that EGFR signaling may play a role in ACC. Neither cell line was particularly sensitive to MDM2 inhibition, indicating that this is not a good target to restore p53 pathway function. Finally, our results suggest that further testing of compounds that target G2/M is warranted, particularly PLK-1 inhibitors.

In vitro chemosensitivity profiling in ACC cell lines

CompoundMechanism of ActionTime PointAverage IC50 for SW-13 in uMAverage IC50 for H295R in uM
Mitotane Unknown, but results in mitochondrial degeneration 72 hours 12.86 9.48 
    96 hours 11.03 9.05 
    120 hours 11.51 9.99 
Nutlin-3 MDM2 inhibitor 72 hours 19.24 15.81 
    96 hours 16.86 14.83 
    120 hours 15.81 14.00 
LY294002 PI3K inhibitor 72 hours 4.36 53.86 
    96 hours 4.31 22.73 
    120 hours 4.80 13.55 
Erlotinib EGF-R inhibitor 72 hours 2.73 NA 
    96 hours 2.56 2.29 
    120 hours 2.66 2.34 
BI-2536 PLK-1 inhibitor 72 hours 0.0059 0.35 
    96 hours ND 0.11 
    120 hours ND 0.12 
VX-680 Aurora kinase inhibitor 72 hours 17.23 ND 
    96 hours 6.07 ND 
    120 hours 5.21 ND 
CompoundMechanism of ActionTime PointAverage IC50 for SW-13 in uMAverage IC50 for H295R in uM
Mitotane Unknown, but results in mitochondrial degeneration 72 hours 12.86 9.48 
    96 hours 11.03 9.05 
    120 hours 11.51 9.99 
Nutlin-3 MDM2 inhibitor 72 hours 19.24 15.81 
    96 hours 16.86 14.83 
    120 hours 15.81 14.00 
LY294002 PI3K inhibitor 72 hours 4.36 53.86 
    96 hours 4.31 22.73 
    120 hours 4.80 13.55 
Erlotinib EGF-R inhibitor 72 hours 2.73 NA 
    96 hours 2.56 2.29 
    120 hours 2.66 2.34 
BI-2536 PLK-1 inhibitor 72 hours 0.0059 0.35 
    96 hours ND 0.11 
    120 hours ND 0.12 
VX-680 Aurora kinase inhibitor 72 hours 17.23 ND 
    96 hours 6.07 ND 
    120 hours 5.21 ND 

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3672.