Abstract 1110: Targeting β-catenin enhances the therapeutic efficacy of osimertinib in EGFR- mutant non-small cell lung cancer (NSCLC)
Authors: Suman Shankar , Guan Shu-Xiao , Navari Nastaran , Arasada Rajeswara Rao , Carbone David P. , Memmott Regan M. 
Published: July 2021

In the US, ~15% of patients with metastatic lung adenocarcinoma have tumors harboring “driver” mutations in the EGFR gene, which demonstrate major clinical responses to EGFR Tyrosine Kinase Inhibitors (TKIs). The third-generation EGFR TKI osimertinib shows superior clinical activity compared to early-generation EGFR TKIs, however, essentially all tumors eventually develop resistance to osimertinib. We previously demonstrated that EGFR TKIs induce “adaptive persistence” in cancer cells with stem-like properties, allowing these cells to survive and acquire resistance. Activation of β-catenin and downstream signaling components is one of the major pathways enabling this adaptive persistence. Our goal is to identify and validate β-catenin inhibitors that have the potential to improve the depth and duration of response to osimertinib in EGFR-mutant NSCLC. We used the EGFR-mutant NSCLC cell lines HCC827, HCC4006, and H1975 to evaluate the effects of treatment with osimertinib and a β-catenin inhibitor, BC2059. Cell viability assays were done to determine the IC50 values of BC2059 in this panel of cell lines. ALDEFLUOR assays were performed to assay for induced stem-ness. We also assessed β-catenin protein levels and downstream signaling events in various treatment conditions. To evaluate the preclinical activity of β-catenin inhibition, we treated mice bearing HCC4006 and HCC827 xenografts with osimertinib alone or in combination with BC2059. Preclinical activity was assessed through progression free survival and overall survival. Our in vitro studies demonstrated that NSCLC cell lines are sensitive to β-catenin inhibition in a time and dose-dependent manner, and the addition of BC2059 to osimertinib enhances tumor cell killing. Osimertinib treatment increased non-phosphorylated and total β-catenin levels in EGFR-mutant cell lines. We further showed that osimertinib treatment induced ALDH activity that was sensitive to β-catenin inhibition in HCC4006 and HCC827 cells. BC2059 decreased osimertinib-induced ALDH positivity by &gt;10 fold in HCC4006 and ~2 fold in HCC827 cells. Osimertinib treatment increased levels of the secreted β-catenin transcriptional target PAI1 in cultured media, which was inhibited by BC2059. Our preclinical studies also demonstrated that the combination of osimertinib and BC2059 decreased tumor recurrence and improved overall survival in mice bearing EGFR-mutant human lung cancer xenografts. Overall, our studies show that osimertinib in combination with the β-catenin inhibitor BC2059 enhances osimertinib efficacy and delays tumor recurrence, possibly by targeting drug-tolerant persistent clones that are enriched for with EGFR TKI treatment alone. These data provide strong rationale for a clinical trial that evaluates the combination of osimertinib and BC2059 in patients with metastatic EGFR-mutant NSCLC.

Citation Format: Shankar Suman, Shu-Xiao Guan, Nastaran Navari, Rajeswara Rao Arasada, David P. Carbone, Regan M. Memmott. Targeting β-catenin enhances the therapeutic efficacy of osimertinib in EGFR- mutant non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1110.