Reference Detail

Ref Type Journal Article
PMID (26224873)
Authors Arqués O, Chicote I, Puig I, Tenbaum SP, Argilés G, Dienstmann R, Fernández N, Caratù G, Matito J, Silberschmidt D, Rodon J, Landolfi S, Prat A, Espín E, Charco R, Nuciforo P, Vivancos A, Shao W, Tabernero J, Palmer HG
Title Tankyrase Inhibition Blocks Wnt/β-Catenin Pathway and Reverts Resistance to PI3K and AKT Inhibitors in the Treatment of Colorectal Cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 22
Issue 3
Date 2016 Feb 01
URL
Abstract Text 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/β-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.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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
NVP-TNKS656 NVP-TNKS656 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
NVP-TNKS656 Tankyrase Inhibitor 9 NVP-TNKS656 is a small molecule that inhibits Tankyrase, resulting in decreased Beta-catenin signaling, and potentially leading to reduced tumor growth (PMID: 26224873).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Y391* nonsense unknown ETV6 Y391* results in a premature truncation of the Etv6 protein at amino acid 391 of 452 (UniProt.org). Y391* has been identified in sequencing studies (PMID: 25344691, PMID: 26224873), but has not been biochemically characterized and therefore, its effect on Etv6 protein function is unknown (PubMed, Jul 2019).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CTNNB1 over exp colon cancer predicted - sensitive NVP-TNKS656 + Triciribine Preclinical - Pdx Actionable In a preclinical study, the combination of NVP-TNKS656 and Triciribine (API-2) inhibited tumor growth in Triciribine (API-2)-resistant patient-derived xenograft (PDX) models of colon cancer with high nuclear CTNNB1 (Beta-catenin) levels (PMID: 26224873). 26224873