Diverse Mechanisms of Resistance against Osimertinib, a Third-Generation EGFR-TKI, in Lung Adenocarcinoma Cells with an EGFR-Activating Mutation

by Selleckchem | Sep 14 2023

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is used as a first-line treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, the mechanisms underlying its anticancer activity, particularly the subsequent development of acquired resistance, are unclear. Herein, we investigated the mechanisms underlying the development of osimertinib resistance by treating NSCLC PC-9 cells (harboring an EGFR-activating mutation) with osimertinib, thereby developing five resistant cell lines, i.e., AZDR3, AZDR6, AZDR9, AZDR11, and AZDR14. The amplification of wild-type EGFR in AZDR3 cells and wild-type EGFR and KRAS in AZDR6 cells was also studied. AZDR3 cells showed dependence on EGFR signaling, in addition to afatinib sensitivity. AZDR9 cells harboring KRASG13D showed sensitivity to MEK inhibitors. Furthermore, combination treatment with EGFR and IGF1R inhibitors resulted in attenuated cell proliferation and enhanced apoptosis. In AZDR11 cells, increased Bim expression could not induce apoptosis, but Bid cleavage was found to be essential for the same. A SHP2/T507K mutation was also identified in AZDR14 cells, and, when associated with GAB1, SHP2 could activate ERK1/2, whereas a SHP2 inhibitor, TNO155, disrupted this association, thereby inhibiting GAB1 activation. Thus, diverse osimertinib resistance mechanisms were identified, providing insights for developing novel therapeutic strategies for NSCLC.

Comments:

The study you mentioned investigated the mechanisms underlying the development of osimertinib resistance in non-small cell lung cancer (NSCLC) cells. They treated NSCLC PC-9 cells, which harbor an EGFR-activating mutation, with osimertinib to develop five resistant cell lines: AZDR3, AZDR6, AZDR9, AZDR11, and AZDR14.

In AZDR3 cells, the researchers observed the amplification of wild-type EGFR. This suggests that the overexpression of EGFR, which is not mutated, may contribute to osimertinib resistance in these cells. Additionally, AZDR3 cells were found to be dependent on EGFR signaling and showed sensitivity to the drug afatinib.

In AZDR6 cells, both wild-type EGFR and KRAS amplification were observed. KRAS is a gene that can drive cancer growth and is associated with resistance to EGFR inhibitors. The presence of KRAS amplification in these cells suggests that it may play a role in osimertinib resistance.

AZDR9 cells harbored a specific KRAS mutation, KRASG13D. Interestingly, these cells showed sensitivity to MEK inhibitors. This suggests that targeting the MEK pathway, which is downstream of KRAS, may be an effective strategy to overcome osimertinib resistance in NSCLC with KRASG13D mutation.

The researchers also investigated combination treatment strategies. They found that combining EGFR and IGF1R inhibitors resulted in reduced cell proliferation and increased apoptosis. This suggests that targeting both EGFR and IGF1R pathways simultaneously may enhance the therapeutic efficacy in osimertinib-resistant NSCLC cells.

In AZDR11 cells, increased Bim expression alone was insufficient to induce apoptosis. However, the cleavage of Bid, a protein involved in apoptosis, was found to be essential for inducing apoptosis in these cells. This finding provides insights into the mechanisms underlying resistance to apoptosis in osimertinib-resistant cells and highlights the importance of Bid cleavage in promoting cell death.

In AZDR14 cells, a SHP2/T507K mutation was identified. When associated with GAB1, SHP2 could activate ERK1/2 signaling pathway, which is known to promote cell growth and survival. The researchers found that inhibiting SHP2 with a specific inhibitor, TNO155, disrupted the association between SHP2 and GAB1, leading to inhibition of GAB1 activation and subsequent suppression of ERK1/2 pathway. This suggests that targeting SHP2 may be a potential therapeutic approach for overcoming osimertinib resistance associated with SHP2 mutations.

Overall, this study identified diverse mechanisms of osimertinib resistance in NSCLC cells. These findings provide valuable insights for developing novel therapeutic strategies to overcome resistance and improve outcomes for patients with EGFR-mutant NSCLC.