Oncogenic signals driven by PIK3R2 in ovarian cancer

Abstract

In the past decades, our understanding of the contribution of genomic aberrations to human cancer development is expanding, facilitating the transition of genotype-directed therapy from proof-of-concept to clinical practice. Ovarian cancer, which is one of the deadliest gynecological malignancies, is characterized by genomic aberrations particularly copy number variations. Identification of driver aberrations as biomarkers and therapeutic targets may open new avenue for ovarian cancer treatment.

PIK3R2 encodes the regulatory subunit p85β of the class IA phosphoinositide 3-kinase and is frequently amplified in many malignancies. PIK3R2 amplification is common in ovarian cancer, and its high expression level is associated with worse patient survival. However, the therapeutic implication of PIK3R2 in cancers and its associated oncogenic mechanisms remain elusive. In this work, the molecular manifestations of PIK3R2 amplification were characterized. PIK3R2 overexpression promotes tumorigenicity of ovarian cancer cells in vitro and in vivo. Omics approaches including RNAseq, proteomics and phosphoproteomics have revealed novel potential targets of p85β.

First, p85β upregulates the protein level of a receptor tyrosine kinase AXL, which in turn induces the downstream oncogenic signaling in PIK3R2-overexpressing ovarian cancer. AXL signals through p110-PDK1-SGK3 to mediate the enhanced tumorigenic phenotypes. Blocking AXL reverses the oncogenic effect of PIK3R2 in vitro and in vivo. Mechanistically, p85β inhibits AXL degradation through autophagy-lysosomal pathway, with the involvement of TRIM2 (an E3 ligase) and OPTN (an autophagy receptor). Multiple anti-AXL drugs have entered clinical trials, thus PIK3R2 might be a potential biomarker of patient stratification for anti-AXL therapy.

Second, apart from targets in the cytosol, a transcriptional regulator BCL2 Associated Transcription Factor 1 (BCLAF1) is upregulated by p85β. BCLAF1 likely regulates the expression of a series of genes that contribute to metastatic capability and cell survival of PIK3R2-overexpressing ovarian cancer cells. Inhibition of BCLAF1 abrogates cell metastasis and sensitizes PIK3R2-overexpressing ovarian cancer cells to TRAIL-induced cell death. p85β interacts with BCLAF1 in the nucleus and may regulate BCLAF1 through protein stability. Further investigations on BCLAF1-mediated signaling events and the nuclear functions of p85β will contribute to an understanding of p85β-mediated oncogenic signaling in the nucleus as well as identification of therapeutic targets.

Collectively, this study has characterized for the first time the functional roles and the therapeutic implication of PIK3R2 amplification in ovarian cancer. The data reveal the cytosolic and nuclear proteins that propagate the oncogenic signals of p85β in ovarian cancer. Blockade of these signals could be effective therapeutic interventions for PIK3R2-amplified ovarian cancer.