Itraconazole Reversing Acquired Resistance to Osimertinib in NSCLC by Inhibiting the SHH/DUSP13B/p‐STAT3 Axis

Abstract There is an urgent necessity to devise efficient tactics to tackle the inevitable development of resistance to osimertinib, which is a third‐generation epidermal growth factor receptor (EGFR) inhibitor used in treating EGFR‐mutant nonsmall cell lung cancer (NSCLC). This study demonstrates that combining itraconazole with osimertinib synergistically reduces the proliferation and migration, enhances the apoptosis of osimertinib‐resistant cells, and effectively inhibits the growth of osimertinib‐resistant tumors. Mechanistically, itraconazole combined with osimertinib promotes the proteasomal degradation of sonic hedgehog (SHH), resulting in inactivation of the SHH/Dual‐specificity phosphatase 13B (DUSP13B)/p‐STAT3 and Hedgehog pathways, suppressing Myc proto‐oncogene protein (c‐Myc). Additionally, DUSP13B interacts with signal transducer and activator of transcription 3 (STAT3) and modulates its phosphorylation. Interestingly, it is observed that SHH overexpression partially rescues the synergistic effects of this combination treatment strategy through the SHH/DUSP13B/p‐STAT3 signaling axis. Moreover, it is found that SHH, (GLI1), p‐STAT3, and DUSP13B play significant predictive roles in osimertinib resistance. In lung adenocarcinoma, p‐STAT3 is positively correlated with SHH but negatively correlated with DUSP13B. Together, these results highlight the crucial role of itraconazole in reversing the acquired resistance to osimertinib and provide a scientific rationale for the therapeutic strategy of combining osimertinib with itraconazole.