Hyperactivated Wnt signaling induces synthetic lethal interaction with Rb inactivation by elevating TORC1 activities

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The retinoblastoma (Rb) tumor suppressor regulates cell proliferation; its inactivation can lead to cancer.
• Understanding pathways interacting with Rb loss is crucial for cancer therapy development.
• Wnt signaling is frequently deregulated in various cancers.

Purpose of the Study:

• To identify novel synthetic lethal interactions with Rb inactivation.
• To investigate the role of Wnt signaling in modulating the effects of Rb loss.
• To explore therapeutic strategies targeting the synthetic lethality between Rb and Wnt signaling.

Main Methods:

• Unbiased genetic screens in Drosophila to identify synthetic lethal interactions.
• Analysis of metabolic gene expression and stress responses.
• Investigation of the mechanistic link involving TORC1 signaling and apoptosis.
• Conservation studies in mammalian cell lines.

Main Results:

• A synthetic lethal interaction between Rb inactivation (rbf mutation) and deregulated Wg/Wnt signaling was identified.
• Deregulated Wnt signaling induced metabolic alterations, hypersensitivity to fasting, and synergistic apoptosis with rbf mutation.
• Hyperactivated Wnt signaling increased TORC1 activity, leading to energy stress and synergistic cell death with rbf.
• Inhibition of TORC1 suppressed this synergistic cell death.
• The synthetic lethality and underlying mechanism were conserved in mammalian cells with Rb and APC inactivation.

Conclusions:

• Elevated TORC1 activity and metabolic stress are key components of the synthetic lethality between Wnt pathway hyperactivation and Rb inactivation.
• This conserved interaction offers potential therapeutic targets for cancers with these genetic alterations.