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.

Homeostasis is achieved by balancing cell survival and death. In cancer cells, especially those carrying driver mutations, the processes and signals that promote apoptosis are inhibited, facilitating the survival and proliferation of these dysregulated cells. Apoptosis induction is an important mechanism underlying the therapeutic efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for EGFR-mutated non-small cell lung cancer (NSCLC). However, the mechanisms by which EGFR-TKIs induce apoptosis have not been fully elucidated. A deeper understanding of the apoptotic pathways induced by EGFR-TKIs is essential for the developing novel strategies to overcome resistance to EGFR-TKIs or to enhance the initial efficacy through therapeutic synergistic combinations. Recently, therapeutic strategies targeting apoptosis have been developed for cancer. Here, we review the state of knowledge on EGFR-TKI-induced apoptotic pathways and discuss the therapeutic strategies for enhancing EGFR-TKI efficiency. We highlight the great progress achieved with third-generation EGFR-TKIs. In particular, combination therapies of EGFR-TKIs with anti-vascular endothelial growth factor/receptor inhibitors or chemotherapy have emerged as promising therapeutic strategies for patients with EGFR-mutated NSCLC. Nevertheless, further breakthroughs are needed to yield an appropriate standard care for patients with EGFR-mutated NSCLC, which requires gaining a deeper understanding of cancer cell dynamics in response to EGFR-TKIs.

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Introduction: While the Tokyo Guidelines 2018 suggest primary stone removal for mild to moderate cholangitis, a guideline for severe acute cholangitis is not mentioned. We, therefore, investigated the clinical outcomes of patients with severe acute cholangitis to confirm the usefulness and safety of primary stone removal. Method: This study included 104 severe acute cholangitis patients without gallstone pancreatitis diagnosed at our institution between January 2014 and December 2020. Patients with percutaneous transhepatic biliary drainage as the primary drainage, bile duct stenosis, and endoscopically unidentified bile duct stones were excluded from this study. The clinical results of 14 patients with primary stone removal (primary group) and 23 patients with elective stone removal (elective group) were then retrospectively examined (excluding abnormal values due to underlying diseases). Results: Upon comparing the patient characteristics between groups, the elective group had significantly higher cardiovascular dysfunction (57% vs 7%; p = 0.004), septic shock (39% vs 0%; p = 0.006), disseminated intravascular coagulation treatment (57% vs 14%; p = 0.016), and positive blood cultures (91% vs 43%; p = 0.006) than those in the primary group. Endoscopic sphincterotomy for naïve papilla (90% vs 21%; p = 0.01) and endoscopic nasobiliary drainage (50% vs 9%; p = 0.014) were higher in the primary group, while endoscopic biliary stenting (7% vs 87%; p < 0.001) was lower than that in the elective group. Discussion: There were no significant differences in adverse events or complete stone removal rates between the two groups. In the primary group, the period from the first endoscopic retrograde cholangiopancreatography to stone removal (0 days vs 12 days; p < 0.001) and hospitalization period (12 days vs 26 days; p = 0.012) were significantly shorter and the hospitalization cost ($7731 vs $18758; p < 0.001) was significantly lower than those in the elective group. Conclusion: If patients are appropriately selected, bile duct stones may be safely removed for the treatment of severe acute cholangitis.