Inhibition of Aurora kinase A activity enhances the antitumor response of beta-catenin blockade in human adrenocortical cancer cells

Adrenocortical cancer (ACC) is a rare and aggressive type of endocrine tumor with high risk of recurrence and metastasis. The overall survival of patients diagnosed with ACC is low and treatment for metastatic stages remain limited to mitotane, which has low efficiency in advanced stages of the disease and is associated with high toxicity. Therefore, identification of new biological targets to improve ACC treatment is crucial. Blockade of the Wnt/beta-catenin pathway decreased adrenal steroidogenesis and increased apoptosis of NCI-H295 human ACC cells, in vitro and in a xenograft mouse model. Aurora kinases play important roles in cell division during the G1-M phase and their aberrant expression is correlated with a poor prognosis in different types of tumors. Hence, we hypothesized that inhibition of aurora kinases activity combined with the beta-catenin pathway blockade would improve the impairment of ACC cell growth in vitro. We studied the combinatorial effects of AMG 900, an aurora kinase inhibitor and PNU-74654, a beta-catenin pathway blocker, on proliferation, survival and tumor progression in multiple ACC cell lines: NCI-H295, CU-ACC1 and CU-ACC2. Exposure of ACC cells to the combination of AMG 900 with PNU-74654 decreased cell proliferation and viability compared to either treatment alone. In addition, AMG 900 inhibited cell invasion and clonogenesis compared to PNU-74654, and the combination showed no greater effects. In contrast, PNU-74654 was more effective in decreasing cortisol secretion. These data suggest that inhibition of aurora kinases activity combined with blockade of the beta-catenin pathway may provide a combinatorial approach for targeting ACC tumors.

 

Comments：

Adrenocortical cancer (ACC) is a rare and aggressive tumor that has limited treatment options, with low efficacy and high toxicity. Therefore, identifying new targets for improving ACC treatment is important. The Wnt/beta-catenin pathway and Aurora kinases are potential targets for inhibiting ACC cell growth.

In this study, the combinatorial effects of AMG 900, an Aurora kinase inhibitor, and PNU-74654, a beta-catenin pathway blocker, were investigated in multiple ACC cell lines (NCI-H295, CU-ACC1, and CU-ACC2). The results showed that the combination of AMG 900 and PNU-74654 had a greater inhibitory effect on cell proliferation and viability compared to either treatment alone. In addition, AMG 900 inhibited cell invasion and clonogenesis, while PNU-74654 was more effective in decreasing cortisol secretion.

These findings suggest that the combination of AMG 900 and PNU-74654 may be a potential therapeutic approach for targeting ACC tumors, and further studies are warranted to evaluate their efficacy in vivo.

Related Products

Cat.No.	Product Name	Information
S2719	AMG-900	AMG 900 is a potent and highly selective pan-Aurora kinases inhibitor for Aurora A/B/C with IC50 of 5 nM/4 nM /1 nM. It is >10-fold selective for Aurora kinases than p38α, Tyk2, JNK2, Met and Tie2. Phase 1.

Related Targets

Aurora Kinase