The mitochondrial citrate carrier, SLC25A1, drives stemness and therapy resistance in non-small cell lung cancer

Abstract

Therapy resistance represents a clinical challenge for advanced non-small cell lung cancer (NSCLC), which still remains an incurable disease. There is growing evidence that cancer-initiating or cancer stem cells (CSCs) provide a reservoir of slow-growing dormant populations of cells with tumor-initiating and unlimited self-renewal ability that are left behind by conventional therapies reigniting post-therapy relapse and metastatic dissemination. The metabolic pathways required for the expansion of CSCs are incompletely defined, but their understanding will likely open new therapeutic opportunities. We show here that lung CSCs rely upon oxidative phosphorylation for energy production and survival through the activity of the mitochondrial citrate transporter, SLC25A1. We demonstrate that SLC25A1 plays a key role in maintaining the mitochondrial pool of citrate and redox balance in CSCs, whereas its inhibition leads to reactive oxygen species build-up thereby inhibiting the self-renewal capability of CSCs. Moreover, in different patient-derived tumors, resistance to cisplatin or to epidermal growth factor receptor (EGFR) inhibitor treatment is acquired through SLC25A1-mediated implementation of mitochondrial activity and induction of a stemness phenotype. Hence, a newly identified specific SLC25A1 inhibitor is synthetic lethal with cisplatin or with EGFR inhibitor co-treatment and restores antitumor responses to these agents in vitro and in animal models. These data have potential clinical implications in that they unravel a metabolic vulnerability of drug-resistant lung CSCs, identify a novel SLC25A1 inhibitor and, lastly, provide the first line of evidence that drugs, which block SLC25A1 activity, when employed in combination with selected conventional antitumor agents, lead to a therapeutic benefit.

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

“…Besides fatty acid desaturation and lipid droplet formation, our analysis also suggests that the fluctuating oxygen levels in the TME73 could also sensitize prostate cancer cells to the inhibition of the mitochondrial citrate transporter SLC25A1 ( Figure 3D). Our model's prediction of SLC25A1's essentiality in hypoxic tumor cells is substantiated by prior findings that SLC25A1 expression is up-regulated when prostate cancer cells are exposed to cycling hypoxia/reoxygenation stress74 Notably, pharmacological inhibition of SLC25A1 sensitizes cancer cells to ionizing radiation, cisplatin or EGFR inhibitor treatments in lung cancer74, 75 . Thus, treating prostate cancer cells in a hypoxic TME with the SLC25A1 inhibitor, 1,2,3-benzene-tricarboxylic acid (BTA) could not only yield direct tumor-specific killing, but it could also potentiate the activity of concomitant radiation or chemotherapy interventions.…”

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

“…Our model's prediction of SLC25A1's essentiality in hypoxic tumor cells is substantiated by prior findings that SLC25A1 expression is up-regulated when prostate cancer cells are exposed to cycling hypoxia/re-oxygenation stress 74 . Notably, pharmacological inhibition of SLC25A1 sensitizes cancer cells to ionizing radiation, cisplatin or EGFR inhibitor treatments in lung cancer 74,75 . Thus, treating prostate cancer cells in a hypoxic TME with the SLC25A1 inhibitor, 1,2,3-benzene-tricarboxylic acid (BTA) could not only yield direct tumor-specific killing, but it could also potentiate the activity of concomitant radiation or chemotherapy interventions.…”

Inhibitors of lipogenic enzymes as a potential therapy against cancer

“…Pharmacological inhibition of SLC25A1 inhibits tumor growth alone and increases sensitivity for chemotherapeutic agents such as cis-platin. 156,157 4.3 | ELOVL6, SCD1, FASD: FA…”