Abstract
Tumours defective in the DNA homologous recombination repair pathway can be effectively treated with poly (ADP-ribose) polymerase (PARP) inhibitors; these have proven effective in clinical trials in patients with BRCA gene function-defective cancers. However, resistance observed in both pre-clinical and clinical studies is likely to impact on this treatment strategy. Over-expression of phosphoglycoprotein (P-gp) has been previously suggested as a mechanism of resistance to the PARP inhibitor olaparib in mouse models of Brca1/2-mutant breast cancer. Here, we report that in a Brca2 model treated with olaparib, P-gp upregulation is observed but is not sufficient to confer resistance. 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. However, resistance is strongly associated with epithelial-mesenchymal transition (EMT) and treatment-naïve tumours given a single dose of olaparib upregulate EMT markers within one hour. Therefore, in this model, olaparib resistance is likely a product of an as-yet unidentified mechanism associated with rapid transition to the mesenchymal phenotype.
Highlights
Cancer cells with specific defective DNA-damage response pathways show synthetic lethality with inhibition of poly (ADP-ribose) polymerase (PARP), a key enzyme in single strand break repair [1, 2]
Tumours defective in the DNA homologous recombination repair pathway can be effectively treated with poly (ADP-ribose) polymerase (PARP) inhibitors; these have proven effective in clinical trials in patients with BRCA gene function-defective cancers
We have previously shown that mammary tumours in a Brca2-mutant mouse model generally respond well to olaparib, but that eventually tumours relapse on treatment [3]
Summary
Cancer cells with specific defective DNA-damage response pathways show synthetic lethality with inhibition of PARP, a key enzyme in single strand break repair [1, 2]. Olaparib has demonstrated excellent anti-tumour activity in Brca-mutated breast cancer models [3, 4] and clinical trials in BRCA-mutated cancer patients have proven efficacious, leading to the approval of olaparib in over 60 countries world-wide (https://www.lynparza.com). Both preclinical and clinical evidence suggest activity in non-BRCA homologous recombination repair (HRR) defective backgrounds [5, 6]. Elucidation of the diverse mechanisms of resistance to PARP inhibition is imperative, so that new approaches for more accurate patient stratification for potential novel combinations or follow-up therapies may be identified
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.