EGFR H1975

Overexpression of MDM2 is a novel resistant mechanism to Osimertinib in EGFR mutant NSCLC. MDM2 utilizes its E3 ligase activity to provoke FBW7 destruction and sequentially leads to MCL-1 stabilization. Cancer cells with aberrant MDM2 state are refractory to apoptosis induction and elicit a resistant phenotype to Osimertinib. Therefore, targeting MDM2 would be a feasible approach to overcome resistance to Osimertinib in EGFR mutant NSCLC.

Furthermore, the RBM15-SPOCK1 axis was activated in drug-tolerant persister cells, indicating that early targeting of RBM15 during EGFR-TKI treatment could dramatically extend the patient response and benefit from TKI therapy. Our results emphasize the critical role of RBM15 in reversing EGFR-TKI resistance and propose it as a promising therapeutic target for prolonging TKI treatment benefits in patients with lung adenocarcinoma.

The nebivolol-gefitinib-loratadine combination may be a promising alternative for lung cancer treatment.

Furthermore, CyH inhibited the activation of JAK3/STAT signaling pathway. Taken together, our findings suggest that CyH promotes the sensitivity to gefitinib in NSCLC cells through the inhibition of EGFR activation and PD-L1 expression.

Anticancer efficacy of PPL, erlotinib (ERL), gefitinib (GEF), and cisplatin (CIS) were investigated in H1299 and H1975 cell lines. Treatment with PPL alone and in combination induced anti-mitogenic and apoptotic responses at the molecular level. PPL sensitized lung cancer cells to EGFR-TKI and induced potent cytotoxic effects at low concentrations.

The establishment of tumoroids from lung cancer cell lines is feasible with various methodologies, which is promising for future tumoroid growth from clinical lung cancer samples. However, analysis of relevant markers is a prerequisite and may need to be validated for each model and cell type.

Patients with lower baseline serum miR-130a-3p concentrations had longer progression-free survival. miR-130a-3p is a potential therapeutic target and a predictive biomarker of osimertinib resistance in adenocarcinomas.

Our results show guttiferone E to be a promising, novel and potent antitumor drug candidate for osimertinib-resistant lung cancer with EGFR L858R/T790M mutations.

This study investigates the repurposing potential of non-nucleosidic reverse transcriptase inhibitors (NNRTIs), specifically Rilpivirine and Etravirine, as L858R/T790M tyrosine kinase inhibitors for addressing acquired resistance in non-small cell lung cancer (NSCLC). Using in silico molecular docking, Rilpivirine demonstrated a docking score of -7.534 kcal/mol, comparable to established epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) like Osimertinib and WZ4002...Enzymatic assays revealed that Rilpivirine inhibited the double mutant epidermal growth factor receptor tyrosine kinase (EGFR TK) with an IC50 value of 54.22 nM and spared the wild-type EGFR TK with an IC50 of 22.52 nM. These findings suggest Rilpivirine's potential as a therapeutic agent for NSCLC with EGFR L858R/T790M mutations.

Moreover, IV-3 showed no inhibitory activity against A431 and A549 cells expressing wild-type EGFR, thereby eliminating potential toxic side effects emerging from wild-type EGFR inhibition. Overall, our study provides promising insights into EGFR-PROTACs as a potential therapeutic strategy against EGFR-acquired mutation.

The results showed that, compared with EGFR wild-type/sensitive mutant cells, EGFR-resistant mutant cells were more sensitive to the ferroptosis inducer, erastin. In the present study, GPX4 inhibitor only or combined with RAD001 inhibited the AKT/mTOR pathway in EGFR-resistant mutant cells. Therefore, the results of the present study suggested that inhibition of the mTOR pathway may downregulate the expression of ferroptosis-related proteins in EGFR-resistant and EGFR wild-type NSCLC cells, increase the ROS and MDA levels and ultimately induce ferroptosis.

Our findings strongly support targeting of GRP78 as a promising therapeutic strategy for NSCLC patients with acquired resistance to EGFR-TKIs.