Gelview Support Osimertinib Resistance Research: PIM1 kinase promotes EMT-associated osimertinib resistance via regulating GSK3β signaling in EGFR-mutant NSCLC

New progress has been made in the study of osimertinib resistance mechanisms in EGFR-mutant non-small cell lung cancer (NSCLC).

Research teams led by Richeng Jiang and Dingzhi Huang from Tianjin Medical University Cancer Institute and Hospital recently published their findings in “Cell Death & Disease” (IF = 9.0, Q1 journal).

This study revealed a novel mechanism by which PIM1 kinase promotes epithelial–mesenchymal transition (EMT)-associated osimertinib resistance through regulation of the GSK3β signaling pathway, providing new therapeutic targets and strategies for overcoming osimertinib resistance in EGFR-mutant NSCLC.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Approximately 10%–15% of Caucasian patients and up to 50% of East Asian patients carry activating mutations in the epidermal growth factor receptor (EGFR). Osimertinib, a third-generation irreversible EGFR tyrosine kinase inhibitor (TKI), targets both EGFR-sensitive mutations (such as exon 19 deletion and L858R mutation) and the EGFR T790M mutation, making it the first-line treatment for EGFR-mutant NSCLC. However, resistance to osimertinib inevitably develops, and one of the major resistance mechanisms is epithelial–mesenchymal transition (EMT). EMT is a biological process characterized by the loss of epithelial cell polarity and intercellular adhesion, which enhances tumor cell migration and invasion, ultimately leading to resistance to targeted therapy and chemotherapy. In addition, PIM1, a serine/threonine kinase, is overexpressed or aberrantly expressed in NSCLC and is involved in tumor proliferation, apoptosis, metastasis, and drug resistance. By affecting the activity of GSK3β (glycogen synthase kinase 3 beta), PIM1 may participate in regulating the EMT process and thereby influence osimertinib resistance. However, the specific role and regulatory mechanism of PIM1 in osimertinib resistance remained unclear.

Therefore, this study uncovered a new mechanism in which PIM1 promotes EMT-associated osimertinib resistance through modulation of the GSK3β signaling pathway. The researchers found that upregulation of PIM1 was significantly associated with enhanced growth, invasion, and drug resistance in osimertinib-resistant cells, as well as with the expression of EMT-related molecules. Mechanistically, PIM1 inhibited GSK3β activity through phosphorylation, thereby suppressing the ubiquitin–proteasome degradation of SNAIL and SLUG, leading to their stabilization and accumulation, which promoted EMT and enhanced osimertinib resistance. In addition, treatment with a PIM1 inhibitor blocked EMT progression and restored sensitivity of osimertinib-resistant NSCLC cells to osimertinib. Clinical sample analysis further demonstrated that the PIM1/GSK3β signaling pathway was activated in osimertinib-resistant NSCLC, while dual EGFR/PIM1 blockade synergistically reversed osimertinib resistance in vivo. These findings indicate that PIM1 is a key driver of EMT-associated osimertinib resistance in NSCLC cells and suggest that combination therapy with PIM1 inhibitors and osimertinib may provide clinical benefits for patients with EGFR-mutant NSCLC.

Experiments using Gelview

In this study, the GelView 6000 Plus Intelligent Imaging Workstation developed by Guangzhou Biolight Co., Ltd. was used for imaging during the detection of multiple protein expression levels, including PIM1, GSK3β, and their phosphorylated forms (p-GSK3β Ser9 and Tyr216).