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

Abstract

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/b-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 b-catenin content. High FOXO3A activity conferred sensitivity to NVP-TNKS656 treatment. Thirteen of 40 patients presented high nuclear b-catenin content and progressed earlier upon PI3K/AKT/ mTOR inhibition. Nuclear b-catenin levels predicted drug response, whereas clinicopathologic traits, gene expression profiles, or frequent mutations (KRAS, TP53, or PIK3CA) did not.Conclusions: High nuclear b-catenin content independently predicts resistance to PI3K and AKT inhibitors. Combined treatment with a Wnt/tankyrase inhibitor reduces nuclear b-catenin, reverts such resistance, and represses tumor growth. FOXO3A content and activity predicts response to Wnt/b-catenin inhibition and together with b-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/b-catenin inhibitors.

MTA3 regulates malignant progression of colorectal cancer through Wnt signaling pathway

“…22 It has been reported that activation of canonical Wnt signaling induced chemoresistance of CRC. 23 In conclusion, this study demonstrated that MTA3 was overexpressed in CRC and correlated with advanced TNM stage and Ki67 proliferation index. MTA3 promoted CRC growth by regulating cell cycle progression and related proteins, including cyclin D1, cyclin E, and p27.…”

Wnt/β-catenin signaling in melanoma: Preclinical rationale and novel therapeutic insights

“…Given the fact that the Wnt pathway almost affects virtually in each type of tissue and organ, it is not surprising that its aberrant activation has been found in many types of malignancy. This is supported by many clinical observations such as 1) A number of β-catenin targeted genes have been found deregulated in ovarian cancer, most of which are pivotal regulators of cell metabolism 25 ; 2) key components along the Wnt/β-catenin axis have been found to be frequently mutated in cancer cells that induce genetic instability, such as deactivation of the tumour suppressor gene APC in colon cancer 26 and oncogenic mutations of β-catenin itself in a few solider tumours such as melanoma 27 ; 3) WNT signaling maintains the phenotypes of cancer stem cell 28 and plays a potential role in EMT 29 that may contribute to acquired resistance to clinical cancer therapies [30][31][32] . In this review, taking melanoma as an example, we will specifically discuss about the roles of WNT signaling, including both canonical and non-canonical pathways, in tumourigenesis and clinical drug resistance, aiming to highlight its importance in future combination therapy.…”

The Discovery and Characterization of K-756, a Novel Wnt/β-Catenin Pathway Inhibitor Targeting Tankyrase

“…It is therefore assumed that this synergistic effect occurs due to Wnt/b-catenin inhibition. A TNKS inhibitor was also reported to show synergistic effects with a MEK inhibitor (18) and a PI3K/Akt inhibitor (41,42). The mechanism underlying these combination effects may be due to crosstalk between the Wnt/b-catenin pathway and the EGFR, MAPK, or Akt pathways.…”