Abstract 38: Molecular determinants of drug response in TNBC cell lines

• Published in: Clinical cancer research Vol. 26; no. 12_Supplement_1; p. 38
• Main Authors: Merrill, Nathan M., Lachacz, Eric J., Vandecan, Nathalie M., Ulintz, Peter J., Bao, Li Wei, Lloyd, John P., Morikawa, Aki, Merajver, Sofia D., Soellner, Matthew B.
• Format: Journal Article
• Language: English
• Published: 15.06.2020
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1557-3265.ADVPRECMED20-38

Abstract Triple-negative breast cancer (TNBC) is one of the deadliest forms of breast cancer due to limited treatment options beyond conventional chemotherapy. TNBC constitutes approximately 10-20% of total breast cancer cases in the US; however, TNBC tends to be more aggressive, higher grade, and have a poorer prognosis than other forms of breast cancer. While oncogenic aberrations have been identified in TNBC, such as the PI3K/AKT/mTOR pathway that is misregulated in ~25% of tumors, there is a general lack of predictive markers of therapeutic efficacy to identify subsets of patients most likely to positively respond to a given targeted or conventional therapy. Simply relying on mutation status is undependable, as some patients without PI3K mutations respond to PI3K inhibitors and some patients with PI3K mutations do not respond. Thus, there is a critical need for biomarkers of drug efficacy in TNBC to help design precision medicine clinical trials based on systematically derived predictive biomarkers. To fill this gap, we devised a strategy to identify biomarkers of drug efficacy in TNBC. Using 23 TNBC cell lines, drug sensitivity scores (DSS3) were determined across a panel of investigational drugs and drugs approved for other indications. Molecular readouts were generated for each cell line using RNA sequencing, RNA targeted panels, DNA sequencing, and functional proteomics. DSS3 values were correlated with molecular readouts using an FDR-corrected significance cutoff of p* < 0.05 and yielded molecular determinant panels that predict anti-TNBC efficacy. Molecular determinant panels were obtained from 12 drugs that were prioritized on the basis of their efficacy. Six molecular determinant panels were obtained by correlating DSS3 with molecular readouts. We found that coinhibiting correlated pathways led to robust synergy across many cell lines. Together, our work presents an integrated method to identify biomarkers of drug efficacy in TNBC, where DNA predictions correlate poorly with drug response. Furthermore, we outline a framework to identify optimal companion drugs for combination therapy. Citation Format: Nathan M. Merrill, Eric J. Lachacz, Nathalie M. Vandecan, Peter J. Ulintz, Li Wei Bao, John P. Lloyd, Aki Morikawa, Sofia D. Merajver, Matthew B. Soellner. Molecular determinants of drug response in TNBC cell lines [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 38.