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

Brandon Luke L. Seagle, Chia Ping Huang Yang, Kevin H. Eng, Monica Dandapani, Oluwatosin Odunsi-Akanji, Gary L. Goldberg, Kunle Odunsi, Susan Band Horwitz, Shohreh Shahabi

Research output: Contribution to journalArticle

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)159-164
Number of pages6
JournalGynecologic Oncology
Volume138
Issue number1
DOIs
StatePublished - Jul 1 2015

Keywords

  • Drug therapy
  • Ovarian neoplasms
  • Survival
  • TP53 genes

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

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