Phosphatidylinositol-3-kinase (PI3K)/Akt Signaling is Functionally Essential in Myxoid Liposarcoma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Myxoid liposarcoma (MLS) is an aggressive soft-tissue tumor driven by the FUS-DDIT3 fusion protein.
• While often lacking somatic mutations, some MLS cases harbor activating PIK3CA mutations.
• The PI3K/Akt signaling pathway is a critical regulator of cell growth and survival.

Purpose of the Study:

• To investigate the prevalence of PI3K/Akt signaling alterations in MLS.
• To evaluate the therapeutic potential of targeting PI3K in MLS.

Main Methods:

• Next-generation sequencing (NGS), FISH, and IHC were used to analyze PI3K/Akt pathway components in a large MLS cohort.
• In vitro studies utilized RNAi and BKM120 (buparlisib) to inhibit PI3K activity in MLS cell lines.
• In vivo efficacy was assessed using an avian chorioallantoic membrane model.

Main Results:

• Activating PI3K/Akt alterations were found in 26.8% of MLS cases, with PIK3CA mutations in 14.2%.
• IHC indicated PI3K/Akt activation in a broader subset, suggesting diverse activation mechanisms.
• PI3K inhibition significantly reduced MLS cell proliferation and viability in vitro and in vivo.

Conclusions:

• PI3K/Akt signaling plays a crucial role in MLS tumorigenesis.
• Targeting PI3K represents a viable therapeutic strategy for MLS, particularly for tumors with specific PI3K/Akt pathway alterations.