Discovery of PARP1-PROTAC as novel strategy against PARP inhibitor
resistance via promoting ferroptosis in mutant-p53 triple-negative
breast cancer
Abstract
Background and Purpose: The acquired resistance to PARP inhibitors
(PARPi) caused by point mutations in PARP1 protein is hard to overcome
through current strategies. In order to explore modalities to conquer
resistance and identify patients who are most likely to benefit from
PARP1-targeted therapy, we developed a proteolysis-targeted-chimaera
(PROTAC) to degrade mutant PARP1 in p53-mutant TNBC. Experimental
Approach: Based on analysis of the resistant mutations, we attempted to
use PROTAC strategy to increase the sensitivity of cells expressing
PARPi-resistant proteins that identified from patients. The
antineoplastic activity of our synthetic degrader was evaluated in
multiple human cell lines, as well as the xenograft model with p53
mutation. The proteomics subsequently was used to reveal the potential
mechanism of the degrader. Ferroptosis, as main mechanism, was assayed
via detecting SLC7A11 signaling, glutathione and lipid peroxidation.
Besides, according to genetic alteration analysis from patients, three
common p53 mutations were selected to assess PARP1-related cell death.
Key Results: We developed a PROTAC termed “NN3”, and this compound
could trigger ubiquitination and proteasome-mediated PARP1 degradation.
Interestingly, compared with other reported PARP1 degraders, NN3 has a
unique antitumor mechanism and it promote ferroptosis effectively via
decreasing the SLC7A11/GPX4 pathway in HR-proficient TNBC cells, whether
or not these cells express drug resistance-related PARP1 mutations. More
importantly, NN3 showed potent activity and low toxicity in vivo studies
on mutant-p53 TNBC. Conclusion and Implications: We identify
PROTAC-mediated degradation of PARP1 as a novel strategy against PARPi
resistance and a paradigm for targeting mutant-p53 cancers by inducing
ferroptosis.