Functional genomics reveals that tumors with activating phosphoinositide 3-kinase mutations are dependent on...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Activating mutations in the phosphoinositide 3-kinase (PI3K) pathway are common in various cancers.
• Understanding non-oncogene dependencies is crucial for developing targeted cancer therapies.

Purpose of the Study:

• To identify synthetic-lethal (SL) genes that are essential for the survival of cancer cells with PI3K pathway mutations.
• To explore novel therapeutic strategies targeting PI3K-driven oncogenesis.

Main Methods:

• Genome-wide RNA interference (RNAi) screening in PI3K wild-type and mutant cell lines.
• Meta-analysis of screening data with other large-scale RNAi datasets.
• Inhibition of identified pathways (ribosomal translation and proteasomal degradation) and assessment of cancer cell viability.
• Analysis of gene expression in human colorectal tumors and correlation with patient survival.

Main Results:

• Ribosomal protein translation and proteasomal protein degradation were identified as critical nononcogene dependencies for PI3K-driven tumors.
• Selective killing of PI3K mutant tumor cells was achieved by inhibiting either translation or degradation pathways, dependent on mTOR signaling.
• Upregulated expression of ribosomal and proteasomal components was observed in human colorectal tumors with PI3K pathway activation.
• A PI3K SL gene signature predicted patient survival in colorectal cancer, particularly in those with PI3K pathway activation.

Conclusions:

• Disruption of protein turnover homeostasis through ribosome or proteasome inhibition represents a potential novel treatment strategy for PI3K mutant cancers.
• Targeting these pathways offers a selective approach to eliminate PI3K-driven tumor cells.
• The findings provide a basis for developing new therapeutic interventions for cancers with activated PI3K signaling.