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

Ted Lau, Emily Chan, Marinella Callow, Jo Waaler, Jason Boggs, Robert A. Blake, Steven Magnuson, Amy Sambrone, Melissa Schutten, Ron Firestein, Ondrej Machon, Vladimir Korinek, Edna Choo, Dolores Diaz, Mark A. Merchant, Paul Polakis, Daniel D. Holsworth, Stefan Krauss, Mike Costa

Research output: Contribution to journalArticleResearchpeer-review

158 Citations (Scopus)

Abstract

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 xenograftmodel 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. Cancer Res; 73(10); 3132-44.

Original languageEnglish
Pages (from-to)3132-3144
Number of pages13
JournalCancer Research
Volume73
Issue number10
DOIs
Publication statusPublished - 15 May 2013
Externally publishedYes

Cite this

Lau, T., Chan, E., Callow, M., Waaler, J., Boggs, J., Blake, R. A., ... Costa, M. (2013). A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. Cancer Research, 73(10), 3132-3144. https://doi.org/10.1158/0008-5472.CAN-12-4562
Lau, Ted ; Chan, Emily ; Callow, Marinella ; Waaler, Jo ; Boggs, Jason ; Blake, Robert A. ; Magnuson, Steven ; Sambrone, Amy ; Schutten, Melissa ; Firestein, Ron ; Machon, Ondrej ; Korinek, Vladimir ; Choo, Edna ; Diaz, Dolores ; Merchant, Mark A. ; Polakis, Paul ; Holsworth, Daniel D. ; Krauss, Stefan ; Costa, Mike. / A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. In: Cancer Research. 2013 ; Vol. 73, No. 10. pp. 3132-3144.
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abstract = "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 xenograftmodel 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. Cancer Res; 73(10); 3132-44.",
author = "Ted Lau and Emily Chan and Marinella Callow and Jo Waaler and Jason Boggs and Blake, {Robert A.} and Steven Magnuson and Amy Sambrone and Melissa Schutten and Ron Firestein and Ondrej Machon and Vladimir Korinek and Edna Choo and Dolores Diaz and Merchant, {Mark A.} and Paul Polakis and Holsworth, {Daniel D.} and Stefan Krauss and Mike Costa",
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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, MA, Polakis, P, Holsworth, DD, Krauss, S & Costa, M 2013, 'A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth', Cancer Research, vol. 73, no. 10, pp. 3132-3144. https://doi.org/10.1158/0008-5472.CAN-12-4562

A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. / Lau, Ted; Chan, Emily; Callow, Marinella; Waaler, Jo; Boggs, Jason; Blake, Robert A.; Magnuson, Steven; Sambrone, Amy; Schutten, Melissa; Firestein, Ron; Machon, Ondrej; Korinek, Vladimir; Choo, Edna; Diaz, Dolores; Merchant, Mark A.; Polakis, Paul; Holsworth, Daniel D.; Krauss, Stefan; Costa, Mike.

In: Cancer Research, Vol. 73, No. 10, 15.05.2013, p. 3132-3144.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth

AU - Lau, Ted

AU - Chan, Emily

AU - Callow, Marinella

AU - Waaler, Jo

AU - Boggs, Jason

AU - Blake, Robert A.

AU - Magnuson, Steven

AU - Sambrone, Amy

AU - Schutten, Melissa

AU - Firestein, Ron

AU - Machon, Ondrej

AU - Korinek, Vladimir

AU - Choo, Edna

AU - Diaz, Dolores

AU - Merchant, Mark A.

AU - Polakis, Paul

AU - Holsworth, Daniel D.

AU - Krauss, Stefan

AU - Costa, Mike

PY - 2013/5/15

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N2 - 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 xenograftmodel 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. Cancer Res; 73(10); 3132-44.

AB - 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 xenograftmodel 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. Cancer Res; 73(10); 3132-44.

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