MUTANT P53 AS A THERAPEUTIC TARGET IN CANCER

Identifying therapeutic approaches to target TP53 mutations has the potential to revolutionize cancer treatment. TP53, the gene that encodes the prominent tumor suppressor protein p53, is mutated and inactivated in half of sporadic human tumors. Additionally, individuals who harbor germline TP53 mutations are at greater risk for developing spontaneous cancer. Within the spectrum of germline TP53 mutations are hypomorphic variants, which are partially inactivated with defective tumor suppressor function. Variants of TP53 are associated with altered sensitivity to canonical chemotherapies, putting patients with mutant p53 at a greater disadvantage regarding clinical outcomes. Our group has previously characterized the P47S hypomorphic variant as a defective tumor suppressor associated with increased cancer risk in African descent individuals, in part due to aberrant phosphorylation for p53 activation and improper regulation of ferroptosis. This work identifies lexibulin as a chemotherapy that preferentially targets P47S tumor cells and describes its mechanism of action as a potential personalized therapeutic approach in individuals harboring the P47S variant. We demonstrate that lexibulin preferentially decreases viability in P47S tumor cells compared to wild type, and our data show that lexibulin significantly induces G1 cell cycle arrest in P47S tumor cells in a manner that is mediated by the peptidyl-prolyl isomerase, PIN1. These findings identify a vulnerability in a single hypomorphic variant of TP53 that can be exploited for improved therapeutic outcomes. In addition to identifying therapeutic approaches that are more efficacious in hypomorphic variants, this work describes the mechanisms of p53-reactivation in mutant p53 ovarian tumor cells by a novel p53 reactivating molecule, SM26.1. Our data show that SM26.1 preferentially targets tumor cells with structural TP53 mutations and restores sensitivity to cisplatin in cisplatin-refractory ovarian tumor cells. Furthermore, we demonstrate that SM26.1 modestly restores transcription-dependent functions of p53 and potently engages p53 in transcription-independent functions by the intrinsic mitochondrial pathway for cell death. This work emphasizes that SM26.1 functions through unique mechanisms compared to canonical p53 reactivating molecules and shows great promise towards improving therapy in aggressive ovarian tumors. Collectively, the combined studies describe strategies for targeting tumor cells with mutant p53.

Author dc:creator

• Foster, Maya, Janae

Advisor dc:contributor.advisor

• Murphy, Maureen, E.

• Biology

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/62713

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/62713