Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition

Area of Science:

• Oncology
• Cell Biology
• Drug Resistance Mechanisms

Background:

• Acquired drug resistance limits cancer therapy efficacy, leading to incomplete responses and relapse.
• Non-mutational mechanisms, particularly the survival of cancer 'persister' cells, are crucial in developing resistance.
• These persister cells form a reservoir for the emergence of drug-resistant tumors.

Purpose of the Study:

• To investigate the mechanisms of cancer persister cell survival and identify therapeutic targets.
• To determine if persister cells share dependencies with previously identified therapy-resistant cell states.
• To evaluate the therapeutic potential of targeting identified dependencies to prevent tumor relapse.

Main Methods:

• Analysis of persister cells derived from various cancer types and drug treatments.
• Assessment of dependency on glutathione peroxidase 4 (GPX4) in therapy-resistant and persister cells.
• In vitro studies involving loss of GPX4 function and subsequent cell death.
• In vivo mouse models to evaluate the impact of GPX4 targeting on tumor relapse.

Main Results:

• Persister cells from diverse cancers and treatments exhibit a therapy-resistant cell state.
• This resistant state confers a dependency on GPX4 for survival.
• Loss of GPX4 function induces selective ferroptotic death in persister cells in vitro.
• Targeting GPX4 prevents tumor relapse in preclinical mouse models.

Conclusions:

• Cancer persister cells acquire a dependency on GPX4, similar to therapy-resistant cells.
• Targeting GPX4 represents a promising strategy to eliminate persister cells and overcome acquired drug resistance.
• Inhibition of GPX4 may serve as a therapeutic approach to prevent tumor relapse in cancer patients.