Tankyrase Inhibition Blocks Wnt/b-Catenin Pathway and Reverts Resistance to PI3K and AKT Inhibitors in the Treatment of Colorectal Cancer

Oriol Arqués, Irene Chicote, Isabel Puig, Stephan P. Tenbaum, Guillem Argilés, Rodrigo Dienstmann, Natalia Fernández, Ginevra Caratù, Judit Matito, Daniel Silberschmidt, Jordi Rodon, Stefania Landolfi, Aleix Prat, Eloy Espín, Ramón Charco, Paolo Nuciforo, Ana Vivancos, Wenlin Shao, Josep Tabernero, Héctor G. Palmer

Research output: Contribution to journalArticleResearchpeer-review

84 Citations (Scopus)

Abstract

© 2015 American Association for Cancer Research. Purpose: Oncogenic mutations in the KRAS/PI3K/AKT pathway are one of the most frequent alterations in cancer. Although PI3K or AKT inhibitors show promising results in clinical trials, drug resistance frequently emerges. We previously revealed Wnt/b-catenin signaling hyperactivation as responsible for such resistance in colorectal cancer. Here we investigate Wnt-mediated resistance in patients treated with PI3K or AKT inhibitors in clinical trials and evaluate the efficacy of a new Wnt/tankyrase inhibitor, NVP-TNKS656, to overcome such resistance. Experimental Design: Colorectal cancer patient-derived sphere cultures and mouse tumor xenografts were treated with NVP-TNKS656, in combination with PI3K or AKT inhibitors.We analyzed progression-free survival of patients treated with different PI3K/AKT/mTOR inhibitors in correlation with Wnt/β-catenin pathway activation, oncogenic mutations, clinicopathological traits, and gene expression patterns in 40 colorectal cancer baseline tumors. Results: Combination with NVP-TNKS656 promoted apoptosis in PI3K or AKT inhibitor-resistant cells with high nuclear β-catenin content. High FOXO3A activity conferred sensitivity to NVP-TNKS656 treatment. Thirteen of 40 patients presented high nuclear β-catenin content and progressed earlier upon PI3K/AKT/ mTOR inhibition. Nuclear β-catenin levels predicted drug response, whereas clinicopathologic traits, gene expression profiles, or frequent mutations (KRAS, TP53, or PIK3CA) did not. Conclusions: High nuclear β-catenin content independently predicts resistance to PI3K and AKT inhibitors. Combined treatment with a Wnt/tankyrase inhibitor reduces nuclear β-catenin, reverts such resistance, and represses tumor growth. FOXO3A content and activity predicts response to Wnt/β-catenin inhibition and together with β-catenin may be predictive biomarkers of drug response providing a rationale to stratify colorectal cancer patients to be treated with PI3K/AKT/mTOR and Wnt/β-catenin inhibitors.
Original languageEnglish
Pages (from-to)644-656
JournalClinical Cancer Research
Volume22
Issue number3
DOIs
Publication statusPublished - 1 Feb 2016

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