SP08-58: Targeting ß-catenin Activity Enhances the Therapeutic Efficacy of the EGFR TKI, osimertinib in EGFR Mutant Non-Small Cell Lung
Rajeswara Rao Arasada
The Ohio State University United States
In the USA approximately 15% of the patients with lung adenocarcinoma have tumors associated with “driver” mutations in the EGFR gene that demonstrate major clinical responses to EGFR Tyrosine Kinase Inhibitors (EGFR TKIs). However, despite the fact that these mutations are always “truncal” and dram
We used multiple EGFR mutant NSCLC cell lines such as HCC827 (E746 - A750 deletion), HCC4006 (L747 - E749 deletion, A750P), H1975 (L858R/T790M double mutations) to analyze the effect of EGFR TKI, osimertinib alone or in combination with ß-catenin inhibitor, BC-2059. We also determined the IC50 value
Treatment of EGFR mutant NSCLC in combination with EGFR TKI, osimertinib and ß-catenin activity inhibitor, BC-2059 showed enhanced killing compared to EGFR TKI alone. We also showed that EGFR TKI mediated ALDH activity was decreased upon treatment with BC-2059 suggesting that inhibition of ß-catenin activity with BC-2059 can overcome EGFR TKI mediated drug persistence in EGFR mutant NSCLC. We have also identified that treatment of various non-small cell lung cancer cells with wild-type EGFR, with BC-2059 showed cell death in a dose dependent manner. Suggesting that BC-2059 may be an ideal drug to treat NSCLC that have no targeted therapy options available. To demonstrate the mechanistical link between EGFR TKI mediated ß-catenin activation we have demonstrated that osimertinib treatment shows an increased non-phospho ß-catenin (active) and total ß-catenin levels in mutant human EGFR Cell lines. We further showed that osimertinib treatment mediated ß-catenin activity is sensitive to BC-2059 treatment in HCC827 cells suggesting that BC-2059 is able to overcome EGFR TKI mediated drug persistence through inhibition of EGFR TKI mediated ß-catenin activity. Similarly, osimertinib induced PAI1 level was downregulated by BC-2059 in a time and dose-dependent manner in HCC827 and HCC4006 cells. To further demonstrate the in vivo relevance, we have performed preclinical studies using EGFR mutant driven tumor xenografts. Our preclinical studies have shown that mice bearing EGFR mutant xenograft tumors treated with the combination of EGFR TKI, osimertinib and ß-catenin activity inhibitor, BC-2059 showed delayed tumor recurrence compared to osimertinib alone. The outcomes of the in vitro study and the preclinical study revealed that the combination treatment of BC-2059 and osimertinib may be more beneficial to EGFR mutant NSCLC patients.
We demonstrated that the combination of EGFR TKI, osimertinib with ß-catenin activity inhibitor delays the tumor recurrence potentially by targeting drug persister clones generated by EGFR TKI treatment. Hence, the use of BC-2059 with osimertinib can be beneficial to enhance the survival of EGFR mutant NSCLC patients.