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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	22	3	2016 Feb 01	644-56	Clin Cancer Res

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	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
NVP-TNKS656		NVP656	Tankyrase Inhibitor 11	NVP-TNKS656 is a small molecule that inhibits Tankyrase, resulting in decreased Beta-catenin signaling, and potentially leading to reduced tumor growth (PMID: 26224873, PMID: 30944457, PMID: 31897238).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

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