Navitoclax combined with Alpelisib effectively inhibits Merkel cell carcinoma cell growth in vitro

Area of Science:

• Oncology
• Dermatology
• Molecular Biology

Background:

• Merkel cell carcinoma (MCC) is an aggressive skin cancer with limited treatment options for non-responsive or recurrent cases.
• Up to 50% of MCC patients do not respond to current therapies, necessitating novel treatment strategies.
• BCL-2 is a key anti-apoptotic protein implicated in cancer cell survival.

Purpose of the Study:

• To evaluate the efficacy of combining Navitoclax (a BCL-2 inhibitor) and Alpelisib (a PI3K p110α inhibitor) in MCC.
• To determine if this drug combination can overcome treatment resistance in MCC.
• To investigate the mechanism of action, including apoptosis induction.

Main Methods:

• Immunohistochemistry was used to assess BCL-2 expression in MCC tissues and cell lines.
• Four MCC cell lines were treated with Navitoclax and Alpelisib, alone and in combination.
• Cell viability was measured using XTT assay, and apoptosis was assessed via cleaved PARP Western blotting and Annexin V staining.

Main Results:

• BCL-2 expression was detected in 94% of MCCs and all tested MCC cell lines.
• Navitoclax monotherapy demonstrated significant efficacy against BCL-2-positive MCC cell lines.
• The combination of Alpelisib and Navitoclax exhibited synergistic and prolonged inhibition of MCC cell viability, inducing apoptosis up to 4 days.

Conclusions:

• BCL-2 is frequently overexpressed in Merkel cell carcinoma, making it a viable therapeutic target.
• The combination of Navitoclax and Alpelisib demonstrates potent synergistic activity, leading to sustained MCC cell death.
• This drug combination represents a novel and promising therapeutic approach for patients with Merkel cell carcinoma.