PI3K as a Potential Therapeutic Target in Thymic Epithelial Tumors.

Introduction: Thymic epithelial tumors (TETs) are rare tumors originating from the epithelium of the thymus with limited therapeutic options beyond surgery. The pathogenesis of TETs is poorly understood, and the scarcity of model systems for these rare tumors makes the study of their biology very challenging.

Methods: A new cell line (MP57) was established from a thymic carcinoma specimen and characterized using standard biomarker analysis, as well as next-generation sequencing (NGS) and functional assays. Sanger sequencing was used to confirm the mutations identified by NGS.

Results: MP57 possesses all the tested thymic epithelial markers and is deemed a bona fide thymic carcinoma cell line. NGS analysis of MP57 identified a mutation in the gene PIK3R2, which encodes a regulatory subunit of PI3K. Further analysis identified different mutations in multiple PI3K subunit genes in another cell line and several primary thymic carcinoma samples, including two catalytic subunits (PIK3CA and PIK3CG) and another regulatory subunit (PIK3R4). Inhibiting PI3K with GDC-0941 resulted in in vitro antitumor activity in TET cells carrying mutant PI3K subunits.

Conclusions: Alterations of PI3K due to mutations in its catalytic or regulatory subunits are observed in a subgroup of TETs, in particular, thymic carcinomas. Targeting PI3K may be an effective strategy to treat these tumors.