AZ1366: An inhibitor of tankyrase and the canonical wnt pathway that limits the persistence of non-small cell lung cancer cells following EGFR inhibition

Hannah A. Scarborough, Barbara A. Helfrich, Matias Casas-Selves, Alwin G. Schuller, Shaun E. Grosskurth, Jihye Kim, Aik-Choon Tan, Daniel C. Chan, Zhiyong Zhang, Vadym Zaberezhnyy, Paul A. Bunn, James De Gregori

Research output: Contribution to journalArticle

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Abstract

Purpose: The emergence of EGFR inhibitors such as gefitinib, erlotinib, and osimertinib has provided novel treatment opportunities in EGFR-driven non-small cell lung cancer (NSCLC). However, most patients with EGFR-driven cancers treated with these inhibitors eventually relapse. Recent efforts have identified the canonical Wnt pathway as a mechanism of protection from EGFR inhibition and that inhibiting tankyrase, a key player in this pathway, is a potential therapeutic strategy for the treatment of EGFR-driven tumors. Experimental Design: We performed a preclinical evaluation of tankyrase inhibitor AZ1366 in combination with multiple EGFR-inhibitors across NSCLC lines, characterizing its antitumor activity, impingement on canonical Wnt signaling, and effects on gene expression. We performed pharmacokinetic and pharmacodynamic profiling of AZ1366 in mice and evaluated its therapeutic activity in an orthotopic NSCLC model. Results: In combination with EGFR inhibitors, AZ1366 syner-gistically suppressed proliferation of multiple NSCLC lines and amplified global transcriptional changes brought about by EGFR inhibition. Its ability to work synergistically with EGFR inhibition coincided with its ability to modulate the canonical Wnt pathway. Pharmacokinetic and pharmacodynamic profiling of AZ1366-treated orthotopic tumors demonstrated clinically relevant serum drug levels and intratumoral target inhibition. Finally, coadministration of an EGFR inhibitor and AZ1366 provided better tumor control and improved survival for Wnt-responsive lung cancers in an orthotopic mouse model. Conclusions: Tankyrase inhibition is a potent route of tumor control in EGFR-dependent NSCLC with confirmed dependence on canonical Wnt signaling. These data strongly support further evaluation of tankyrase inhibition as a cotreatment strategy with EGFR inhibition inan identifiable subset of EGFR-driven NSCLC.

Original languageEnglish
Pages (from-to)1531-1541
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number6
DOIs
Publication statusPublished - 2017 Mar 15
Externally publishedYes

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Tankyrases
Wnt Signaling Pathway
Non-Small Cell Lung Carcinoma
Neoplasms
Pharmacokinetics
Therapeutics
Lung Neoplasms
Research Design
Gene Expression
Recurrence
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Scarborough, H. A., Helfrich, B. A., Casas-Selves, M., Schuller, A. G., Grosskurth, S. E., Kim, J., ... De Gregori, J. (2017). AZ1366: An inhibitor of tankyrase and the canonical wnt pathway that limits the persistence of non-small cell lung cancer cells following EGFR inhibition. Clinical Cancer Research, 23(6), 1531-1541. https://doi.org/10.1158/1078-0432.CCR-16-1179

AZ1366 : An inhibitor of tankyrase and the canonical wnt pathway that limits the persistence of non-small cell lung cancer cells following EGFR inhibition. / Scarborough, Hannah A.; Helfrich, Barbara A.; Casas-Selves, Matias; Schuller, Alwin G.; Grosskurth, Shaun E.; Kim, Jihye; Tan, Aik-Choon; Chan, Daniel C.; Zhang, Zhiyong; Zaberezhnyy, Vadym; Bunn, Paul A.; De Gregori, James.

In: Clinical Cancer Research, Vol. 23, No. 6, 15.03.2017, p. 1531-1541.

Research output: Contribution to journalArticle

Scarborough, HA, Helfrich, BA, Casas-Selves, M, Schuller, AG, Grosskurth, SE, Kim, J, Tan, A-C, Chan, DC, Zhang, Z, Zaberezhnyy, V, Bunn, PA & De Gregori, J 2017, 'AZ1366: An inhibitor of tankyrase and the canonical wnt pathway that limits the persistence of non-small cell lung cancer cells following EGFR inhibition', Clinical Cancer Research, vol. 23, no. 6, pp. 1531-1541. https://doi.org/10.1158/1078-0432.CCR-16-1179
Scarborough, Hannah A. ; Helfrich, Barbara A. ; Casas-Selves, Matias ; Schuller, Alwin G. ; Grosskurth, Shaun E. ; Kim, Jihye ; Tan, Aik-Choon ; Chan, Daniel C. ; Zhang, Zhiyong ; Zaberezhnyy, Vadym ; Bunn, Paul A. ; De Gregori, James. / AZ1366 : An inhibitor of tankyrase and the canonical wnt pathway that limits the persistence of non-small cell lung cancer cells following EGFR inhibition. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 6. pp. 1531-1541.
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AU - Casas-Selves, Matias

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AU - Grosskurth, Shaun E.

AU - Kim, Jihye

AU - Tan, Aik-Choon

AU - Chan, Daniel C.

AU - Zhang, Zhiyong

AU - Zaberezhnyy, Vadym

AU - Bunn, Paul A.

AU - De Gregori, James

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N2 - Purpose: The emergence of EGFR inhibitors such as gefitinib, erlotinib, and osimertinib has provided novel treatment opportunities in EGFR-driven non-small cell lung cancer (NSCLC). However, most patients with EGFR-driven cancers treated with these inhibitors eventually relapse. Recent efforts have identified the canonical Wnt pathway as a mechanism of protection from EGFR inhibition and that inhibiting tankyrase, a key player in this pathway, is a potential therapeutic strategy for the treatment of EGFR-driven tumors. Experimental Design: We performed a preclinical evaluation of tankyrase inhibitor AZ1366 in combination with multiple EGFR-inhibitors across NSCLC lines, characterizing its antitumor activity, impingement on canonical Wnt signaling, and effects on gene expression. We performed pharmacokinetic and pharmacodynamic profiling of AZ1366 in mice and evaluated its therapeutic activity in an orthotopic NSCLC model. Results: In combination with EGFR inhibitors, AZ1366 syner-gistically suppressed proliferation of multiple NSCLC lines and amplified global transcriptional changes brought about by EGFR inhibition. Its ability to work synergistically with EGFR inhibition coincided with its ability to modulate the canonical Wnt pathway. Pharmacokinetic and pharmacodynamic profiling of AZ1366-treated orthotopic tumors demonstrated clinically relevant serum drug levels and intratumoral target inhibition. Finally, coadministration of an EGFR inhibitor and AZ1366 provided better tumor control and improved survival for Wnt-responsive lung cancers in an orthotopic mouse model. Conclusions: Tankyrase inhibition is a potent route of tumor control in EGFR-dependent NSCLC with confirmed dependence on canonical Wnt signaling. These data strongly support further evaluation of tankyrase inhibition as a cotreatment strategy with EGFR inhibition inan identifiable subset of EGFR-driven NSCLC.

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