Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition

By M. Hangauer, V. Viswanathan, M. Ryan, Dhruv Bole, J. Eaton, A. Matov, Jacqueline Galeas, Harshil Dhruv, Michael E. Berens, Stuart L. Schreiber and 2 more. Nature, 2017

642 citations recorded by the source corpus.

Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the survival of residual cancer ‘persister’ cells. The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse. We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival. Here we show that a similar therapy-resistant cell state underlies the behaviour of persister cells derived from a wide range of cancers and drug treatments. Consequently, we demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance.

Subfields: Cell Biology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/ee432f3421fe775a54f839eb8d1d2a2767ef1ec7

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Oncology

1. Brent R. Stockwell
2. Scott J. Dixon
3. R. Kang
4. D. Tang

In Pulmonary and Respiratory Medicine

1. Brent R. Stockwell
2. Scott J. Dixon
3. D. Tang
4. R. Kang
5. M. Conrad

Citations in the corpus

• Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State (2019, neutral): “Recent studies show that a more mesenchymal phenotype, de-differentiation, and acquired resistance to targeted inhibitors, can all promote a ferroptosissensitive cell state (Hangauer et al., 2017; Tsoi et al., 2018; Viswanathan et al., 2017).”
• Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, positive): “Aggressive cancers that have undergone epithelial-to-mesenchymal transition are more susceptible to ferroptosis (Viswanathan et al., 2017), and resistance to targeted agents that induce apoptosis is associated with increased sensitivity to ferroptosis (Hangauer et al., 2017).”