Rapid activation of epithelial-mesenchymal transition drives PARP inhibitor resistance in Brca2-mutant mammary tumours

The cover for issue 27 of Oncotarget features Figure 11, "Olaparib-resistant tumours do not have Rad51 foci," by Ordonez, et al.

Over-expression of phosphoglycoprotein has been previously suggested as a mechanism of resistance to the PARP inhibitor olaparib in mouse models of Brca1/2-mutant breast cancer.

Furthermore, resistant/relapsed tumours do not show substantial changes in PK/PD of olaparib, do not downregulate PARP1 or re-establish double stranded DNA break repair by homologous recombination, all previously suggested as mechanisms of resistance.

Dr. Matthew J. Smalley from the European Cancer Stem Cell Research Institute, at Cardiff University, in Cardiff, UK said "Cancer cells with specific defective DNA-damage response pathways show synthetic lethality with inhibition of PARP, a key enzyme in single strand break repair."

Olaparib has demonstrated excellent anti-tumour activity in Brca-mutated breast cancer models and clinical trials in BRCA-mutated cancer patients have also proven efficacious, leading to the approval of olaparib in over 60 countries world-wide.

The researchers found that the initial response to olaparib treatment is a very rapid activation of a mesenchymal-like differentiation program and, indeed, that either an initial weak response to olaparib treatment, or acquired resistance following an initial good response, correlated primarily with epithelial-to-mesenchymal transition , where epithelial cells lose their cell-cell adhesion and apical-basal polarity and convert into mesenchymal-like cells.

Tumours with EMT features have been shown to be highly resistant to chemotherapies and the author?s data suggest that EMT is associated with both intrinsic and acquired resistance to olaparib.

Therefore, in this model, olaparib resistance is likely a product of an as-yet unidentified mechanism associated with the mesenchymal phenotype.

The Smalley research team concluded, "A recent study in small cell lung cancer identified a link between EMT and resistance to PARP inhibitors in that disease setting and PARP-1 has been shown to regulate EMT in prostate cancer models through regulation of TGF signalling and changes in levels of ZEB1."

Full text - https://doi.org/10.18632/oncotarget.26830

Correspondence to - Matthew J. Smalley - [email protected]

Keywords - PARP inhibitors, olaparib, Brca2, EMT, P-gps