Abstract 2073: A systematic investigation of the effect of scheduling of targeted combination therapies on response and dynamics of relapse in triple negative breast cancer cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.2073-2073
• Main Authors: Patwardhan, Gauri A., Wali, Vikram B., Pusztai, Lajos, Hatzis, Christos
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-2073

Cancer treatment typically involves administration of combination of targeted therapies, but initial response is often followed by disease relapse. The efficacy of a treatment regimen depends on the complex interplay between cancer growth dynamics, drug specificity and kinetics, treatment dose and its scheduling. In standard high-throughput drug screening assays, cells are treated with a single drug cocktail bolus and cell viability is assessed after 2-3 days, thus not considering treatment interactions and long-term effects. Recently we have reported a promising synergistic combination of crizotinib (ALK/MET inhibitor) and ABT-263 (BCL2/BCL-XL inhibitor) against triple negative breast cancer cells. To understand the effect of the sequence and combination doses of crizotnib and ABT-263, we designed a comprehensive experimental plan that involved a total of 567 treatment regimens by varying treatment duration with the first drug (1, 2, or 3 days), followed by drug withdrawal and recovery period (2, 5 or 10 days) and then by a second cycle of treatment and recovery periods over a 26-day period. Cell viability was assessed by the CellTiter-Glo luminescence assay. Interestingly, ABT-263 alone induced higher cytotoxicity than an equivalent dose of crizotinib, but the remaining viable cells recovered much faster after ABT-263 withdrawal than cells after crizotinib withdrawal. Furthermore, cells exposed to higher doses of ABT-263 eventually become less sensitive to crizotinib. Among sequential regimens, crizotinib followed by ABT-263 was significantly more effective than ABT-263 followed by crizotinib, and combinations that included lower doses of ABT-263 were most effective. Taken together, our results show a significant interaction between the two targeted therapies, and suggest that it may be possible to select treatment scheduling that can delay drug resistance and tumor relapse in vivo. Note: This abstract was not presented at the meeting. Citation Format: Gauri A. Patwardhan, Vikram B. Wali, Lajos Pusztai, Christos Hatzis. A systematic investigation of the effect of scheduling of targeted combination therapies on response and dynamics of relapse in triple negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2073. doi:10.1158/1538-7445.AM2017-2073