PMID- 25958320 OWN - NLM STAT- MEDLINE DCOM- 20150820 LR - 20190221 IS - 1095-6859 (Electronic) IS - 0090-8258 (Print) IS - 0090-8258 (Linking) VI - 138 IP - 1 DP - 2015 Jul TI - TP53 hot spot mutations in ovarian cancer: selective resistance to microtubule stabilizers in vitro and differential survival outcomes from The Cancer Genome Atlas. PG - 159-64 LID - S0090-8258(15)00868-9 [pii] LID - 10.1016/j.ygyno.2015.04.039 [doi] AB - OBJECTIVE: To test if TP53 hot spot mutations (HSMs) confer differential chemotherapy resistance or survival outcomes, the effects of microtubule stabilizers on human ovarian carcinoma cells (OCCs) expressing TP53 HSMs were studied in vitro. Survival outcomes of patients with high grade serous epithelial ovarian carcinoma (HGS EOC) expressing matched HSMs were compared using The Cancer Genome Atlas (TCGA) data. METHODS: Growth inhibition of OCCs transfected with a HSM (m175, m248 or m273) was measured during treatment with paclitaxel, epothilone B (epoB), or ixabepilone. Effects of epoB on p53 expression, phosphorylation, and acetylation, as well as p53-regulated expression of p21 and mdm2 proteins, were determined by Western blot analysis. Expression of p53 target genes P21, GADD45, BAX, PIDD, NF-kB2, PAI-1, and MDR1 was measured by RT-PCR. cBioPortal.org identified patients with codon R175, R248 or R273 HSMs from TCGA data. Survival outcomes were characterized. RESULTS: p53-m248 confers chemoresistance and is not acetylated during epoB treatment. m273 demonstrated high MDR1 expression and resistance to paclitaxel. P21, GADD45 and PAI-1 expression were down-regulated in mutant OCCs. Optimally cytoreduced patients with codon R273 (n=17), R248 (n=13), R175 (n=7) HSMs, or any other TP53 mutation demonstrated median 14.9, 17.6, 17.8 and 16.9months (p=0.806) progression free survival and 84.1, 33.6, 62.1 and 44.5months (p=0.040) overall survival, respectively. CONCLUSIONS: Human OCCs harboring different TP53 HSMs were selectively resistant to microtubule stabilizers. Patients with different HSMs had significantly different overall survival. Both in vitro data and clinical experience support further studying the outcomes of particular TP53 HSMs. CI - Copyright (c) 2015 Elsevier Inc. All rights reserved. FAU - Seagle, Brandon-Luke L AU - Seagle BL AD - Department of Obstetrics, Gynecology and Reproductive Sciences, Western Connecticut Health Network, 24 Hospital Avenue, Danbury, CT 06810, USA. FAU - Yang, Chia-Ping Huang AU - Yang CP AD - Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Obstetrics and Gynecology and Women's Health, Division of Gynecologic Oncology, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY 10461, USA. FAU - Eng, Kevin H AU - Eng KH AD - Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. FAU - Dandapani, Monica AU - Dandapani M AD - Department of Obstetrics, Gynecology and Reproductive Sciences, Western Connecticut Health Network, 24 Hospital Avenue, Danbury, CT 06810, USA. FAU - Odunsi-Akanji, Oluwatosin AU - Odunsi-Akanji O AD - Department of Obstetrics, Gynecology and Reproductive Sciences, Western Connecticut Health Network, 24 Hospital Avenue, Danbury, CT 06810, USA. FAU - Goldberg, Gary L AU - Goldberg GL AD - Department of Obstetrics and Gynecology and Women's Health, Division of Gynecologic Oncology, Albert Einstein College of Medicine and Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY 10461, USA. FAU - Odunsi, Kunle AU - Odunsi K AD - Department of Gynecologic Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. FAU - Horwitz, Susan Band AU - Horwitz SB AD - Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. FAU - Shahabi, Shohreh AU - Shahabi S AD - Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Prentice Women's Hospital, Northwestern University Feinburg School of Medicine, 250 E Superior Street, Suite 05-2168, Chicago, IL 60611, USA. Electronic address: Shahabi.shohreh@northwestern.edu. LA - eng GR - P50 CA159981/CA/NCI NIH HHS/United States GR - P30 CA016056/CA/NCI NIH HHS/United States GR - P50CA159981-01A1/CA/NCI NIH HHS/United States GR - K01LM012100/LM/NLM NIH HHS/United States GR - P30 CA060553/CA/NCI NIH HHS/United States GR - 1R01CA158318-01A1/CA/NCI NIH HHS/United States GR - K01 LM012100/LM/NLM NIH HHS/United States GR - R01 CA158318/CA/NCI NIH HHS/United States GR - P30CA016056/CA/NCI NIH HHS/United States GR - 2P30 CA016056-36/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20150506 PL - United States TA - Gynecol Oncol JT - Gynecologic oncology JID - 0365304 RN - 0 (Epothilones) RN - 0 (TP53 protein, human) RN - 0 (Tubulin Modulators) RN - 0 (Tumor Suppressor Protein p53) RN - K27005NP0A (ixabepilone) RN - P88XT4IS4D (Paclitaxel) RN - UEC0H0URSE (epothilone B) SB - IM MH - Carcinoma, Ovarian Epithelial MH - Cell Death/drug effects MH - Cell Line, Tumor MH - Drug Resistance, Neoplasm/genetics MH - Epothilones/pharmacology MH - Female MH - *Genes, p53 MH - Humans MH - Middle Aged MH - *Mutation MH - Neoplasms, Glandular and Epithelial/*drug therapy/*genetics MH - Ovarian Neoplasms/*drug therapy/*genetics MH - Paclitaxel/pharmacology MH - Tubulin Modulators/*pharmacology MH - Tumor Suppressor Protein p53/genetics PMC - PMC5303002 MID - NIHMS844087 OTO - NOTNLM OT - Drug therapy OT - Ovarian neoplasms OT - Survival OT - TP53 genes COIS- statement The study authors have no conflicts of interest to declare. EDAT- 2015/05/11 06:00 MHDA- 2015/08/21 06:00 PMCR- 2017/02/10 CRDT- 2015/05/11 06:00 PHST- 2015/03/05 00:00 [received] PHST- 2015/04/29 00:00 [accepted] PHST- 2015/05/11 06:00 [entrez] PHST- 2015/05/11 06:00 [pubmed] PHST- 2015/08/21 06:00 [medline] PHST- 2017/02/10 00:00 [pmc-release] AID - S0090-8258(15)00868-9 [pii] AID - 10.1016/j.ygyno.2015.04.039 [doi] PST - ppublish SO - Gynecol Oncol. 2015 Jul;138(1):159-64. doi: 10.1016/j.ygyno.2015.04.039. Epub 2015 May 6.