A Wnt/?-catenin signaling inhibitor, IMU1003, suppresses the emergence of osimertinib-resistant colonies from gefitinib-resistant non-small cell lung cancer cells

Drug resistance has become a challenge in effective longterm molecular targeted therapy. Longterm nonsmall cell lung cancer (NSCLC) treatments with the first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) shorten the effective duration of the third-generation EGFR-TKI, osimertinib, via genetic or epigenetic mechanisms in addition to the gatekeeper mutation T790M. This study reproduced this persistence in vitro using gefitinib-resistant NSCLC PC-9 cells (GR cells) and revealed that pharmacological nuclear localization inhibition of fi-catenin suppressed the osimertinib resistance. Osimertinib effectively reduced GR cell survival but left significantly more resistant colonies than parental PC-9 cells. The nuclear fraction of fi-catenin was enriched in GR cells during acquisition of osimertinib resistance. A chemical nuclear localization inhibitor of fi-catenin, IMU1003, dramatically decreased the emergence of osimertinib-resistant colonies. Forced nuclear localization of fi-catenin reduced IMU1003 efficacy. Thus, suppression of the nuclear fi-catenin function may overcome the transgenerational EGFR-TKI-resistance.

Automated summary

Drug resistance poses a challenge in molecular targeted therapy. In this study, the resistance to osimertinib was reproduced in vitro using gefitinib-resistant NSCLC cells (GR cells), and it was found that inhibition of nuclear localization of fi-catenin suppressed osimertinib resistance. The nucleus-associated fi-catenin was enriched in GR cells during the acquisition of osimertinib resistance.