Background: P53 is the most commonly mutated protein in cancer with more than 40% of all cancer patients harboring a p53 mutation. Up to 85% of triple-negative breast cancers (TNBCs), aggressive breast cancers characterized by the absence of ER, PR, and Her2 receptors, have p53 mutations. P53 is a tumor suppressor that helps balance cellular growth and death after a genomic insult. Due to the rate of p53 mutation in cancer, the targeting of p53 in a clinical setting is an attractive option. However, currently there are no available p53-targeted drugs. We hypothesized that molecular pathways exist, that when inhibited, induce death or suppress growth of p53-mutant breast cancer cells, without affecting p53 wild-type breast cells. To investigate this hypothesis, we conducted a high-throughput drug screen to identify drugs that induce death or suppress growth of p53-mutant TNBCs.
Methods: A library of 453 drugs with diverse and known mechanisms of action was used to perform high-throughput drug screening through collaboration with Texas A&Ms Center for Translational Cancer Research. An ATP luminescence assay was used to test eight TNBC cell lines with distinct p53 mutations in this screen. We then tested a subset of these drugs, identified to have an effect on p53-mutant TNBC, on the growth of five p53 wild-type breast cancer cell lines. Cell death assays to differentiate between growth suppression and death-inductive phenotypes are currently underway.
Results: 145 drugs were identified that induce death or decrease growth by a minimum of 50% in p53-mutant TNBC cell lines. Of these drugs, 16 drugs were found to differentially suppress the growth of p53-mutant breast cancer cells, as compared to p53-wild type breast cancer cells. Further analysis of these drugs identified proteasome, apoptosis, and iron-dependent cell death pathways as potential p53-mutant specific targets in TNBCs.
Conclusion: A screen of molecularly annotated drugs was performed in p53-mutant and p53-wild type breast cancer cells to identify drugs that preferentially kill or suppress the growth of p53-mutant breast cancers. These studies identified 145 drugs that were able to induce death or decrease growth by a minimum of 50% in p53-mutant TNBC cell lines. Testing these drugs in p53 wild-type breast cancer cell lines demonstrated that several of the identified drugs suppress growth or induce death preferentially in p53-mutant, as compared to p53 wild-type, breast cancers. These drugs affect specific cellular pathways such as proteasomal degradation, ferroptosis, and apoptosis pathways, which appear to be critical for the growth and survival of p53-mutant breast cancers. Further work will elucidate the interplay between p53-mutation and the identified cellular pathways. These studies will provide the basic science foundation for the development of new drugs for the treatment of p53-mutant breast cancer. This work was supported by a generous gift from the John Charles Cain Family.
Citation Format: William Miska Tahaney, Reid Powell, Nghi Nguyen, Lakshmi Reddy Bollu, Jing Qian, Abhijit Mazumdar, Clifford Stephan, Peter JA Davies, Powel H Brown. Identification of drugs that induce the death or suppress the growth of p53-mutant breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-03-08.