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Updated: Feb 11, 2026
Primary Culture of Rat Adrenocortical Cells and Assays of Steroidogenic Functions
Published on: March 12, 2019
Strategic combination therapy overcomes tyrosine kinase coactivation in adrenocortical carcinoma
Chi-Iou Lin1, Edward E Whang, Jacob Moalem
1Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
Background:
Coactivation of tyrosine kinase limits the efficacy of tyrosine kinase inhibitors. We hypothesized that a strategic combination therapy could overcome tyrosine kinase coactivation and compensatory oncogenic signaling in patients with adrenocortical carcinoma (ACC).
Methods:
We profiled 88 tyrosine kinases before and after treatment with sunitinib in H295R and SW13 ACC cells. The effects of monotherapy and strategic combination regimens were determined by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (ie, MTS) assay.
Results:
The minimum inhibitory concentrations (IC(min)) of sunitinib quenched its primary targets: FLT-3, VEGFR-2, and RET. In contrast, ERK, HCK, Chk2, YES, CREB, MEK, MSK, p38, FGR, and AXL were hyperactivated. Monotherapy with sunitinib or PD98059 at their IC(min) reduced proliferation by 23% and 19%, respectively, in H295R cells and by 25% and 24%, respectively, in SW13 cells. Sunitinib and PD98059 in combination decreased proliferation by 68% and 64% in H295R and in SW13 cells, respectively (P < .05 versus monotherapy). The effects of combination treatment exceeded the sum of the effects observed with each individual agent alone.
Conclusion:
We describe the first preclinical model to develop strategic combination therapy to overcome tyrosine kinase coactivation in ACC. Because many tyrosine kinase inhibitors are readily available, this model can be immediately tested in clinical trials for patients with advanced ACC.
Insights
Strategic combination therapy overcomes tyrosine kinase coactivation in adrenocortical carcinoma (ACC). This preclinical model combining sunitinib and PD98059 shows significant proliferation reduction and can advance to clinical trials.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Tyrosine kinase coactivation limits the effectiveness of tyrosine kinase inhibitors.
- Adrenocortical carcinoma (ACC) exhibits compensatory oncogenic signaling.
- A strategic combination therapy approach is hypothesized to overcome these limitations.
Purpose of the Study:
- To investigate a combination therapy to overcome tyrosine kinase coactivation in ACC.
- To evaluate the efficacy of sunitinib and PD98059 combination in ACC cell lines.
Main Methods:
- Profiling of 88 tyrosine kinases before and after sunitinib treatment in H295R and SW13 ACC cells.
- Assessing monotherapy and combination regimen effects using the MTS assay.
- Determining minimum inhibitory concentrations (IC(min)) for agents.
Main Results:
- Sunitinib inhibited primary targets FLT-3, VEGFR-2, and RET, but led to hyperactivation of other kinases (e.g., ERK, AXL).
- Monotherapy with sunitinib or PD98059 showed modest proliferation reduction (19-25%).
- Combination therapy significantly decreased proliferation (64-68%) exceeding the additive effects of monotherapy (P < .05).
Conclusions:
- A novel preclinical model for strategic combination therapy in ACC was developed.
- This model effectively overcomes tyrosine kinase coactivation and compensatory signaling.
- The strategy is ready for immediate clinical trial testing in advanced ACC patients.
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