Fig. 8: Mechanistic summary and targeting approaches for overcoming chemoresistance.
From: Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer
In the hypoxic, chemoresistant TNBC tumor microenvironment, hypoxia induces HIF-1α which then increases the transcription of LOX. LOX, on one hand, increases the expressions of ITGA5 and its ligand, fibronectin in tumor cells and on the other hand, it induces collagen cross-linking and fibronectin fibril assembly leading to reduced drug penetration into tumor cells. In meantime, hypoxia-mediated downregulation of miR-142-3p, which directly targets HIF1A, LOX and ITGA5, leads to further activation of the HIF1A/LOX/ITGA5/FN1 axis. Overall, this culminates in the activation of FAK/Src signaling, blockage of drug-induced apoptosis and chemoresistance in TNBCs. Therefore, using inhibitors targeting LOX (e.g. BAPN) or its downstream FAK (e.g. PF-562271) or Src (Saracatinib) could overcome chemoresistance in TNBCs.
