Abstract 5238: Acquired therapeutic resistance is mediated by deregulation of multiple pathways.

Abstract

Abstract The HER2-directed antibody, trastuzumab combined with chemotherapy, has markedly improved outcome of patients with HER2-amplified breast cancer, yet both de novo and acquired resistance occur in a substantial subset of patients. To study the molecular underpinnings of acquired resistance, we have developed a panel of 30 unique HER2+ cell lines that have been cultured to become resistant to lapatinib, trastuzumab and the combination treatment. Each of these models underwent next-generation sequencing to elucidate mechanisms of resistance to HER2 therapies. We hypothesized that resistance may be mediated by modulation of particular pathways - rather than by individual genes. With this idea in mind, we performed a PARADIGM pathway analysis that integrates information from multiple genomic data types to calculate pathway activity scores. The PARADIGM SuperPathways represent 1321 cell signaling pathways curated from sources such as KEGG, BioCarta, and Reactome. We populated the networks with the copy number (ExomeSeq) and expression (RNAseq) datasets that had been normalized to identify contrasts between parental and resistant lines. For each pathway, we computed a Pathway Activity Score as the sum of the absolute value of each node in the pathway, normalized by the total number of pathway nodes. Nearly 30% of the curated pathways (361/1321) are strongly deregulated in at least one of the network models, whereas a much smaller subset (3%) were strongly deregulated across multiple resistance cell line models. Frequently deregulated pathways include hemoglobin chaperone, ATM mediated phosphorylation of repair proteins, the HIF2alpha transcription factor network and the PLK signaling events in the cell cycle. All together, these findings indicate that resistance is mediated through many signaling mechanisms. Furthermore, the acquired resistance-related aberrations suggest possible second-line treatment strategies that may be effective. Citation Format: Laura M. Heiser, Chad A. Shaw, Nicholas J. Wang, Catie Grasso, Pavana Anur, Sam Ng, Theodore Goldstein, Paul T. Spellman, Joshua Stuart, Kent Osborne, Joe Gray, Rachel Schiff. Acquired therapeutic resistance is mediated by deregulation of multiple pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5238. doi:10.1158/1538-7445.AM2013-5238