In vitro response of primary breast carcinoma cultures to sunitinib.

Abstract

e11524 Background: Sunitinib is a small molecule inhibitor that targets multiple receptor tyrosine kinases, aiming to block tumor proliferation and/or angiogenesis. The proteins and pathways inhibited by sunitinib include: PDGFRα, PDGFRβ, VEGFR1, VEGFR2, VEGFR3, KIT, FLT3, CSF-1R, and RET. Sunitinib is FDA-approved for the treatment of renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GIST). It is currently being evaluated for clinical efficacy in other solid tumor types, such as breast. Because the reported clinical response rates of sunitinib are low to moderate, an integrated biomarker that aids in identifying patients likely to exhibit a positive response to the drug would be a useful clinical tool. The current study investigates the use of an in vitro biological response marker to predict the response of primary cultures of human breast tumors to sunitinib. Methods: In order to characterize the performance of sunitinib in vitro, initial development was performed using the immortalized ovarian carcinoma cell line SKOV3. Subsequently, thirty-nine (39) primary breast carcinoma cultures were studied. All primary specimens treated with sunitinib consisted of a majority of epithelial cells (>65%) as determined by immunocytochemistry. A 10 dose range of drug concentrations was used to treat the cells for 72 hours. After treatment, the cultures were fixed with ethanol, and stained with DAPI. Any cells remaining adherent after treatment were considered live, and the DAPI stained nuclei were counted. The resulting dose response curves were analyzed. Results: The cell line SKOV3 was found to exhibit a consistent response to sunitinib. Dose response curves of the 39 breast specimens revealed that 7.6% (3 of 39) were responsive to sunitinib, 20.5% (8 of 39) of specimens exhibited an intermediate response, and 71.7% (28 of 39) were non-responsive to the drug. Conclusions: The data collected from the primary breast carcinoma cultures and cell line were consistent with the reported clinical response rate of sunitinib in breast cancer. The described biological response marker may contribute to the current chemotherapy identification and selection process for oncologists and their patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Precision Therapeutics