Ceritinib increases sensitivity of AKT inhibitors to gastric cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Gastric cancer (GC) has high morbidity and mortality, with limited efficacy of traditional treatments.
• Over-activation of AKT signaling is a common molecular hallmark in GC.
• Existing AKT inhibitors (AKTIs) show limited success due to compensatory signaling pathways.

Purpose of the Study:

• To investigate the efficacy of combining Ceritinib with AKT inhibitors in gastric cancer.
• To explore the underlying mechanisms of this combination therapy.
• To identify novel therapeutic strategies for gastric cancer.

Main Methods:

• In vitro and in vivo studies using GC cell lines and patient-derived cells.
• Assessment of cell proliferation, apoptosis, and protein phosphorylation levels (p-AKT, p-GSK3β).
• Evaluation of tumor regression in a mouse xenograft model.

Main Results:

• Ceritinib demonstrated a synergistic antitumor effect with AKT inhibitors (Capivasertib, Afuresertib).
• The combination significantly reduced GC cell proliferation and enhanced apoptosis.
• Tumor regression was observed in vivo, with decreased p-AKT and p-GSK3β levels.

Conclusions:

• Ceritinib can overcome AKT inhibitor resistance by targeting compensatory pathways.
• This combination strategy offers a novel therapeutic approach for gastric cancer.
• Further clinical investigation of Ceritinib and AKT inhibitors is warranted for GC treatment.