"Having discovered the importance of the GDNF-RET pathway in forming resistance to hormone therapy, the researchers believe that switching off this pathway in the clinic will increase the effectiveness of aromatase inhibitor treatment for women with breast cancer."
Hi Johan...how do you switch it off? I am on Anastrozole but I think it has stopped being effective
Hi Mk,
I'd get in touch with Professor Clare Isacke:
https://www.icr.ac.uk/our-research/researchers-and-teams/professor-clare-isacke
Anastrozole Regulates Fatty Acid Synthase in Breast Cancer
Abstract
Our previous matched case-control study of postmenopausal women with resected early-stage breast cancer revealed that only anastrozole, but not exemestane or letrozole, showed a significant association between the 6-month estrogen concentrations and risk of breast cancer. Anastrozole, but not exemestane or letrozole, is a ligand for estrogen receptor α. (this means that anastrozole is estrogenic) The mechanisms of endocrine resistance are heterogenous and with the new mechanism of anastrozole, we have found that treatment of anastrozole maintains fatty acid synthase (FASN) protein level by limiting the ubiquitin-mediated FASN degradation, leading to increased breast cancer cell growth. Mechanistically, anastrozole decreases the guided entry of tail-anchored proteins factor 4 (GET4) expression, resulting in decreased BCL2-associated athanogene cochaperone 6 (BAG6) complex activity, which in turn, prevents RNF126-mediated degradation of FASN. Increased FASN protein level can induce a negative feedback loop mediated by the MAPK pathway. High levels of FASN are associated with poor outcome only in patients with anastrozole-treated breast cancer, but not in patients treated with exemestane or letrozole. Repressing FASN causes regression of breast cancer cell growth. The anastrozole-FASN signaling pathway is eminently targetable in endocrine-resistant breast cancer.
https://doi.org/10.1158/1535-7163.mct-21-0509
Review on target domains and natural compound-based inhibitors of fatty acid synthase for anticancer drug discovery
Abstract
Cancer cells require a higher amount of energy in the form of fatty acids for their uncontrolled proliferation and growth. Fatty acid synthase (FASN) plays a crucial role in the synthesis of palmitate, which is involved in most of the critical malignant pathways. Hence, by targeting FASN, tumour growth can be controlled. By designing and developing FASN inhibitors with catalytic domain specificity, safe and potential anticancer drugs can be achieved. The article draws light towards the catalytic domains of FASN, their active site residues and interaction of some of the reported natural FASN inhibitors (resveratrol, lavandulyl flavonoids, catechins, stilbene derivatives, etc). The rationality (structure-activity relationship) behind the variation in the activity of the reported natural FASN inhibitors (butyrolactones, polyphenolics, galloyl esters and thiolactomycins) has also been covered. Selective, safe and potentially active FASN inhibitors could be developed by: (i) having proper understanding of the function of all catalytic domains of FASN (ii) studying the upstream and downstream FASN regulators (iii) identifying cancer-specific FASN biomarkers (that are non-essential/absent in the normal healthy cells) (iv) exploring the complete protein structure of FASN, e-screening of the compounds prior to synthesis and study their ADME properties (v) predicting the selectivity based on their strong affinity at the catalytic site of FASN.
https://doi.org/10.1111/cbdd.13942
Orlistat is also a FASN inhibitor. FASN expression is partially controlled by sterol regulatory element-binding protein (SREBP), so a combination of FASN and SREBP inhibitors may be a strategy in the treatment of anastrozole-resistant breast cancer. Previous studies showed that Dipyridamole inhibits SREBP activation.
Thanks!
