TANKYRASE Inhibition Enhances the Antiproliferative Effect of PI3K and EGFR Inhibition, Mutually Affecting β-CATENIN and AKT Signaling in Colorectal Cancer.

Overactivation of the WNT/β-CATENIN signaling axis is a common denominator in colorectal cancer. Currently, there is no available WNT inhibitor in clinical practice. Although TANKYRASE (TNKS) inhibitors have been proposed as promising candidates, there are many colorectal cancer models that do not respond positively to TNKS inhibition in vitro and in vivo Therefore, a combinatorial therapeutic approach combining a TNKS inhibitor (G007-LK) with PI3K (BKM120) and EGFR (erlotinib) inhibitors in colorectal cancer was investigated. The data demonstrate that TNKS inhibition enhances the effect of PI3K and EGFR inhibition in the TNKS inhibitor-sensitive COLO320DM, and in the nonsensitive HCT-15 cell line. In both cell lines, combined TNKS/PI3K/EGFR inhibition is more effective at reducing growth than a dual TNKS/MEK inhibition. TNKS/PI3K/EGFR inhibition affected in a context-dependent manner components of the WNT/β-CATENIN, AKT/mTOR, EGFR, and RAS signaling pathways. TNKS/PI3K/EGFR inhibition also efficiently reduced growth of both COLO320DM and HCT-15 tumor xenografts in vivo At the highest doses, tumor xenograft growth was halted without affecting the body weight of the tested animals.Implications: Combining TNKS inhibitors with PI3K and EGFR inhibition may expand the therapeutic arsenal against colorectal cancers. Mol Cancer Res; 16(3); 543-53. ©2017 AACR.

Solberg NT ，Waaler J ，Lund K ，Mygland L ，Olsen PA ，Krauss S ... -  《-》

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

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.

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 ... -  《-》

A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth.

Most colorectal cancers (CRC) are initiated by mutations of APC, leading to increased β-catenin-mediated signaling. However, continued requirement of Wnt/β-catenin signaling for tumor progression in the context of acquired KRAS and other mutations is less well-established. To attenuate Wnt/β-catenin signaling in tumors, we have developed potent and specific small-molecule tankyrase inhibitors, G007-LK and G244-LM, that reduce Wnt/β-catenin signaling by preventing poly(ADP-ribosyl)ation-dependent AXIN degradation, thereby promoting β-catenin destabilization. We show that novel tankyrase inhibitors completely block ligand-driven Wnt/β-catenin signaling in cell culture and display approximately 50% inhibition of APC mutation-driven signaling in most CRC cell lines. It was previously unknown whether the level of AXIN protein stabilization by tankyrase inhibition is sufficient to impact tumor growth in the absence of normal APC activity. Compound G007-LK displays favorable pharmacokinetic properties and inhibits in vivo tumor growth in a subset of APC-mutant CRC xenograft models. In the xenograft model most sensitive to tankyrase inhibitor, COLO-320DM, G007-LK inhibits cell-cycle progression, reduces colony formation, and induces differentiation, suggesting that β-catenin-dependent maintenance of an undifferentiated state may be blocked by tankyrase inhibition. The full potential of the antitumor activity of G007-LK may be limited by intestinal toxicity associated with inhibition of Wnt/β-catenin signaling and cell proliferation in intestinal crypts. These results establish proof-of-concept antitumor efficacy for tankyrase inhibitors in APC-mutant CRC models and uncover potential diagnostic and safety concerns to be overcome as tankyrase inhibitors are advanced into the clinic.

Lau T ，Chan E ，Callow M ，Waaler J ，Boggs J ，Blake RA ，Magnuson S ，Sambrone A ，Schutten M ，Firestein R ，Machon O ，Korinek V ，Choo E ，Diaz D ，Merchant M ，Polakis P ，Holsworth DD ，Krauss S ，Costa M ... -  《-》

The Anti-Tumor Activity of Succinyl Macrolactin A Is Mediated through the β-Catenin Destruction Complex via the Suppression of Tankyrase and PI3K/Akt.

Regmi SC ，Park SY ，Kim SJ ，Banskota S ，Shah S ，Kim DH ，Kim JA ... -  《PLoS One》

Phospholipase D1 Inhibition Linked to Upregulation of ICAT Blocks Colorectal Cancer Growth Hyperactivated by Wnt/β-Catenin and PI3K/Akt Signaling.

Purpose: Dysregulated expression of PLD1 has emerged as a hallmark feature of colorectal cancer, which remains a major cause of mortality worldwide. Aberrant activation of Wnt/β-catenin signaling is a critical event in the development of colorectal cancer. Here, we investigated molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways via inhibitor of β-catenin and T-cell factor (ICAT), a negative regulator of Wnt/β-catenin signaling. We also explored the effect of PLD1 inhibition on growth of colorectal cancer hyperactivated by Wnt/β-catenin and PI3K/Akt signaling.Experimental Design: Expression of ICAT via targeting of PLD1 was assessed in vivo in ApcMin/+ mice, an AOM/DSS model, and in vitro using various colorectal cancer cells. The relationship between ICAT/PLD1 expression and prognostic survival value of 153 colorectal cancer patients was examined. The therapeutic efficacy of PLD1 inhibitor was determined using a patient-derived xenograft model carrying APC and PI3K mutations.Results: PLD1 promoted the Wnt/β-catenin signaling pathway by selectively downregulating ICAT via the PI3K/Akt-TopBP1-E2F1 signaling pathways. Low PLD1 expression and high ICAT expression were significantly associated with increased survival in colorectal cancer patients and vice versa. Furthermore, PLD1 inhibition suppressed growth of colorectal cancer activated by the Wnt/β-catenin and PI3K signaling pathways.Conclusions: These results suggest that PLD1 linked to ICAT mediates molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways and thus could be proposed as a novel colorectal cancer prognostic biomarker. These results may assist in the clinical development of a PLD1 inhibitor for treatment of colorectal cancer patients carrying APC and PI3KCA mutations. PLD1, a nodal modifier, acts as a potential therapeutic target for the treatment of colorectal cancer hyperactivated by the Wnt/β-catenin and PI3K/Akt signaling pathways. Clin Cancer Res; 23(23); 7340-50. ©2017 AACR.

Kang DW ，Lee BH ，Suh YA ，Choi YS ，Jang SJ ，Kim YM ，Choi KY ，Min DS ... -  《-》