Under the supervision of Camille Faure, team Vascular Cell Biology in Infection, Inflammation and Cancer
Abstract:
Overexpression of the HER2 tyrosine kinase receptor is found in 20-30% of breast cancers, and HER2 abnormalities leading to its overexpression or activation are also frequently detected in many other cancers. Several anti-HER2 therapies have been developed, based on monoclonal antibodies and kinase inhibitors, and have improved the survival prognosis of patients. However, the toxicity and the rapid onset of resistance mechanisms limit the use and effectiveness of these approaches. HSP90 inhibitors, a chaperone protein essential for many cellular processes and involved in the stability of HER2, effectively induce HER2 degradation but are associated with significant toxic effects due to their low specificity. Their use in humans has not been approved, and the development of new strategies to combat HER2-positive tumors remains relevant.
Previous work by the team shows that ERMs (Ezrin/Radixin/Moesin), by interacting with the juxtamembrane region of HER2, allosterically inhibit HER2 homodimers, and this mechanism is significantly reduced in HER2-positive tumors. My thesis work has identified a new ERMmimetic compound, ebselen oxide, and demonstrated its role as an allosteric inhibitor of HER2 in HER2-positive breast, stomach, and ovarian cancers, but also on mutated forms of HER2 resistant to current therapies. This inhibition results in reduced tumor progression in vitro and in vivo. Furthermore, my work proves that ebselen oxide has additive effects when combined with monoclonal antibodies against HER2 and tyrosine kinase inhibitors, indicating that the juxtamembrane segment of HER2 is a novel target site for anti-HER2 therapies.
I also identified hsa-miR-429 as a diagnostic and prognostic marker for HER2-positive cancers and demonstrated its involvement in regulating the expression and function of HER2. Using a proteomic approach, I identified an HSP40 protein as a target of this miRNA, involved in the regulation of HER2 expression in HER2-positive breast cancers. Its expression level is inversely correlated with HER2 in breast cancers and appears to be predictive of survival outcome in HER2-positive breast cancers. This protein acts via a novel mechanism of HER2 destabilization, chaperone-mediated autophagy (CMA), which limits HER2 expression in HER2-negative breast cancers and non-tumor cells. In HER2-positive tumors, the high expression of hsa-miR-429 inhibits this pathway, contributing to HER2 stabilization. This work raises many questions about the physiological roles of hsa-miR-429, this HSP40 protein, and CMA in regulating HER2 expression in various tissues and the deregulation of this mechanism in HER2-positive cancers.
My work has established that targeting hsa-miR-429 should be considered for the treatment of HER2-positive tumors, a strategy that should be significantly more selective and less harmful than blocking HSP90. Overall, my work proposes new therapeutic approaches targeting HER2 in cancers and improves our understanding of the mechanisms involved in the deregulation of HER2 expression.
Keywords : HER2, cancer, targeted therapies, hsa-miR-429, HSP40
