AZ1366: An Inhibitor of Tankyrase and the Canonical Wnt Pathway that Limits the Persistence of Non–Small Cell Lung Cancer Cells Following EGFR Inhibition

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 anti-tumor activity, impingement on canonical Wnt signaling and effects on gene expression. We performed pharmacokinetic (PK) and pharmacodynamic (PD) profiling of AZ1366 in mice and evaluated its therapeutic activity in an orthotopic NSCLC model. Results In combination with EGFR-inhibitors, AZ1366 synergistically 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. PK and PD profiling of AZ1366-treated orthotopic tumors demonstrated clinically-relevant serum drug levels and intratumoral target inhibition. Finally, co-administration 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 co-treatment strategy with EGFR inhibition in an identifiable subset of EGFR-driven NSCLC.

Urea Cycle Sustains Cellular Energetics upon EGFR Inhibition in EGFR-Mutant NSCLC

“…3A), it significantly impacted cell-cycle profiles of both PC9 and HCC4006 EGFR-mutant cell lines. Knockdown of CPS1 by itself did not significantly affect cell-cycle progression, while treatment with erlotinib led to an increase in G 1 phase and a decrease in S phases as has been shown previously (34). Importantly, knockdown of CPS1 with EGFR inhibition led to a further increase of cells in G 1 phase in PC9 and a further decrease in S phase in HCC4006 and to a lesser extent PC9 cells ( Fig.…”

Sjögren syndrome/scleroderma autoantigen 1 is a direct Tankyrase binding partner in cancer cells

“…The enzyme TNKS1 and the closely related paralog TNKS2, which is less abundant, but was still identified in HeLa cells, are poly-ADP-ribosyltransferases involved in various processes such as telomere length regulation 53 , mitotic spindle formation 54 , proteasomal degradation 55,56 , vesicle trafficking 57 , and Wnt signaling pathway 6 AXIN1 and AXIN2, two key components of the β-catenin destruction complex 6 . The inhibition of TNKS1 catalytic activity antagonizes Wnt signaling and has promising implications for cancer therapy, particularly colorectal cancer and non-small cell lung cancer 6,58,59 . Tankyrase is also crucial for embryonic development and adult homeostasis 60 .…”

Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex

“…(c) β-Catenin fold induction is essential for the activation of β-catenin target genes [119][120][121] . (d) Increased AXIN1 by Tankyrase inhibitor suppresses cell proliferation of cancer cells where Wnt/β-catenin signaling is genetically hyperactive 43,90,93,95,122 . (e) Mutations in RNF43 and ZNRF3 E3 ligases that degrade Wnt receptors contribute to tumor development 111,115 .…”