Abstract
Abstract Farnesyltransferase inhibitors (FTIs) are a class of anticancer drugs that have exhibited modest activity in the clinic as single agents, but were found to have promising activity in combination with the microtubule-stabilizing drug Taxol (TX), both in vitro and in vivo. Clinical trials with an FTI/TX combination have demonstrated a clinical benefit for a subset of patients refractory to previous taxane-treatment. However, the precise cellular machinery underlying the FTI/TX synergistic drug combination still needs to be elucidated. To this end, we undertook an unbiased experimental/computational approach designed to identify the key cellular components that either contribute to or drive the therapeutic synergy of this drug combination. The approach combined (i) measurements of drug-mediated changes on tubulin biomarkers and overall survival; (ii) whole-genome transcriptome analysis using the combination index drug synergy algorithm; (iii) utilization of interaction and functional databases to identify pathway connections and (iv) a reverse-engineering forward simulation (REFS) approach to identify genes that drive synergy. Drug-induced transcriptome changes were examined using whole-genome Affymetrix HGU133 Plus 2 microarrays. Gene changes deemed significant using a fold change criterion, identified as synergistic with the combination index analysis, and their biological relevance was assessed by experimental validation by qPCR and siRNA studies. Also, the transcriptome changes unique to the LNF/TX combination were evaluated in the context of detailed molecular interaction maps and groups of biological function. Our analyses identified several major network hubs that include: (i) overexpression of the class II β-tubulin isotype TUBB2A and of several heat shock protein such as HSP40 and HSP70 and (ii) synergistic overexpression of cell cycle genes CDKN1A and MDM2 (iii) through REFS modeling, prosaposin and granulin were identified as drivers of drug synergy (iv) induction of the focal adhesion molecule paxillin (PXN). Interestingly, stable knockdown of protein farnesyltransferase mimicked the effects of FTI treatment and resulted in strong substratum attachment and migration defects suggesting that PXN could be regulated by farnesyltransferase and its pharmacologic inhibitors. Ultimately, we plan to check the expression levels of the key genes in tumor biopsies from patients enrolled in the Phase 1 FTI/Taxotere clinical trial and correlate their expression in pre- and post-treatment biopsies with clinical response to the combination chemotherapy. Herein, we demonstrate a combined experimental and computational approach that includes functional analysis, data-driven simulation and experimental validation, and its power to identify key cellular components, both known and novel, in the anticancer activity of drug combinations exhibiting therapeutic synergy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4911. doi:10.1158/1538-7445.AM2011-4911
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