Synthetic lethal metabolic targeting of cellular senescence in cancer therapy

Area of Science:

• Oncology
• Cell Biology
• Metabolism

Background:

• Activated oncogenes and chemotherapy induce cellular senescence, a state of terminal growth arrest.
• Therapy-induced senescence (TIS) improves outcomes but senescent tumor cells require elimination.
• Senescence involves histone modifications like H3K9me3 and is linked to the senescence-associated secretory phenotype (SASP).

Purpose of the Study:

• To elucidate the mechanism of metabolic reprogramming in TIS.
• To explore therapeutic exploitation of metabolic vulnerabilities in TIS.
• To investigate the role of Suv39h1 in TIS-dependent metabolic changes.

Main Methods:

• Utilized the Eµ-myc transgenic mouse lymphoma model.
• Compared TIS-competent and TIS-incompetent (Suv39h1(-)) lymphomas.
• Analyzed glucose utilization, ATP production, proteotoxic stress, endoplasmic reticulum stress, unfolded protein response (UPR), and ubiquitination.
• Assessed sensitivity to glucose utilization and autophagy inhibition.
• Investigated caspase-12 and caspase-3 mediated apoptosis.
• Employed pharmacological targeting in vivo.

Main Results:

• TIS-competent lymphomas showed increased glucose utilization and ATP production compared to TIS-incompetent lymphomas.
• This metabolic shift was linked to proteotoxic stress, SASP, endoplasmic reticulum stress, UPR, and increased ubiquitination.
• TIS lymphomas were selectively eliminated by blocking glucose utilization or autophagy, inducing apoptosis.
• Pharmacological targeting of these metabolic demands led to tumor regression and improved outcomes.

Conclusions:

• TIS exhibits a hypercatabolic nature driven by proteotoxic stress and SASP.
• Metabolic vulnerabilities in TIS, specifically glucose utilization and autophagy, are therapeutically exploitable.
• Synthetic lethal metabolic targeting represents a promising strategy for enhancing cancer therapy outcomes.