Brandon-Luke L Seagle1, Chia-Ping Huang Yang2, Kevin H Eng3, Monica Dandapani1, Oluwatosin Odunsi-Akanji1, Gary L Goldberg4, Kunle Odunsi5, Susan Band Horwitz6, Shohreh Shahabi7. 1. Department of Obstetrics, Gynecology and Reproductive Sciences, Western Connecticut Health Network, 24 Hospital Avenue, Danbury, CT 06810, USA. 2. 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. 3. Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. 4. 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. 5. Department of Gynecologic Oncology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. 6. Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. 7. 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.
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 16.9months (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.
OBJECTIVE: To test if TP53 hot spot mutations (HSMs) confer differential chemotherapy resistance or survival outcomes, the effects of microtubule stabilizers on humanovarian 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.
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