Repurposed drug combination of two FDA approved drugs shows potential in triple-negative breast cancer
A recent Nature paper demonstrating that a combination of two FDA-approved drugs, Hemin (marketed as Panhematin) and Metformin, can be effective against triple negative breast cancer and potentially other tumors.
Mechanism proposed by the authors:
- BACH1 pathway, increased in expression in tumours from patients with TNBC, targets mitochondrial
metabolism. BACH1 decreases glucose utilization in the tricarboxylic acid cycle and negatively regulates transcription of electron transport chain (ETC) genes.
- BACH1 depletion by shRNA or degradation by hemin sensitizes cells to ETC inhibitors such
as metformin, suppressing growth of both cell line and patientderived tumour xenografts.
The Nature article title is: Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism and can be found here http://sci-hub.tw/https://www.nature.com/articles/s41586-019-1005-x
Mitochondrial metabolism is an attractive target for cancer therapy1,2. Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options, such as triple-negative breast cancer (TNBC)1,3. Here we show that BTB and CNC homology1 (BACH1)4, a haem-binding transcription factor that is increased in expression in tumours from patients with TNBC, targets mitochondrial metabolism. BACH1 decreases glucose utilization in the tricarboxylic acid cycle and negatively regulates transcription of electron transport chain (ETC) genes. BACH1 depletion by shRNA or degradation by hemin sensitizes cells to ETC inhibitors such as metformin5,6, suppressing growth of both cell line and patient-derived tumour xenografts. Expression of a haem-resistant BACH1 mutant in cells that express a short hairpin RNA for BACH1 rescues the BACH1 phenotype and restores metformin resistance in hemin-treated cells and tumours7. Finally, BACH1 gene expression inversely correlates with ETC gene expression in tumours from patients with breast cancer and in other tumour types, which highlights the clinical relevance of our findings. This study demonstrates that mitochondrial metabolism can be exploited by targeting BACH1 to sensitize breast cancer and potentially other tumour tissues to mitochondrial inhibitors.
The marked inverse correlation between BACH1 and ETC gene expression in individual patients raises the possibility that these biomarkers may be useful for prediction of metformin therapeutic outcome. Our findings also suggest a potential combination therapeutic strategy by repurposing two FDA approved drugs, hemin and metformin (Fig. 4g). Targeting the BACH1 pathway represents a novel approach to enhance the efficacy of inhibitors of mitochondrial metabolism through restriction of metabolic plasticity. More generally, we propose reprogramming the metabolic network to decrease metabolic variance and increase the fraction of cells with increased dependence on mitochondrial respiration. This approach could also be applied to other tumour types that use BACH1 or other key regulators of mitochondrial metabolism.