TP53 hot spot mutations in ovarian cancer: Selective resistance to microtubule stabilizers in vitro and differential survival outcomes from The Cancer Genome Atlas

• Published in: Gynecologic oncology Vol. 138; no. 1; pp. 159 - 164
• Main Authors: Seagle, Brandon-Luke L, Yang, Chia-Ping Huang, Eng, Kevin H, Dandapani, Monica, Odunsi-Akanji, Oluwatosin, Goldberg, Gary L, Odunsi, Kunle, Horwitz, Susan Band, Shahabi, Shohreh
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2015
• Subjects: Carcinoma, Ovarian Epithelial; Cell Death - drug effects; Cell Line, Tumor; Drug Resistance, Neoplasm - genetics; Drug therapy; Epothilones - pharmacology; Female; Genes, p53; Hematology, Oncology and Palliative Medicine; Humans; Middle Aged; Mutation; Neoplasms, Glandular and Epithelial - drug therapy; Neoplasms, Glandular and Epithelial - genetics; Obstetrics and Gynecology; Ovarian neoplasms; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Paclitaxel - pharmacology; Survival; TP53 genes; Tubulin Modulators - pharmacology; Tumor Suppressor Protein p53 - genetics; Drug therapy; Ovarian neoplasms; Survival; TP53 genes
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2015.04.039

Abstract 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 16.9 months (p = 0.806) progression free survival and 84.1, 33.6, 62.1 and 44.5 months (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.