title: PRP4K is a HER2-regulated modifier of taxane sensitivity.
abstract: The taxanes are used alone or in combination with anthracyclines or platinum drugs to treat breast and ovarian cancer, respectively. Taxanes target microtubules in cancer cells and modifiers of taxane sensitivity have been identified in vitro, including drug efflux and mitotic checkpoint proteins. Human epidermal growth factor receptor 2 (HER2/ERBB2) gene amplification is associated with benefit from taxane therapy in breast cancer yet high HER2 expression also correlates with poor survival in both breast and ovarian cancer. The pre-mRNA splicing factor 4 kinase PRP4K (PRPF4B), which we identified as a component of the U5 snRNP also plays a role in regulating the spindle assembly checkpoint (SAC) in response to microtubule-targeting drugs. In this study, we found a positive correlation between PRP4K expression and HER2 status in breast and ovarian cancer patient tumors, which we determined was a direct result of PRP4K regulation by HER2 signaling. Knock-down of PRP4K expression reduced the sensitivity of breast and ovarian cancer cell lines to taxanes, and low PRP4K levels correlated with in vitro-derived and patient acquired taxane resistance in breast and ovarian cancer. Patients with high-grade serous ovarian cancer and high HER2 levels had poor overall survival; however, better survival in the low HER2 patient subgroup treated with platinum/taxane-based therapy correlated positively with PRP4K expression (HR = 0.37 [95% CI 0.15-0.88]; p = 0.03). Thus, PRP4K functions as a HER2-regulated modifier of taxane sensitivity that may have prognostic value as a marker of better overall survival in taxane-treated ovarian cancer patients.
authors.affiliation: a Department of Biochemistry & Molecular Biology ; Dalhousie University ; Halifax , NS Canada.
authors.forename: Dale P
authors.initials: DP
authors.lastname: Corkery
authors.forename: Cécile
authors.initials: C
authors.lastname: Le Page
authors.forename: Liliane
authors.initials: L
authors.lastname: Meunier
authors.forename: Diane
authors.initials: D
authors.lastname: Provencher
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.forename: Graham
authors.initials: G
authors.lastname: Dellaire
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000401:mortality; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D005784:Gene Amplification; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000401:mortality; D017239:Paclitaxel / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017414:Ribonucleoprotein, U4-U6 Small Nuclear / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D017414:Ribonucleoprotein, U4-U6 Small Nuclear; C508053:ERBB2 protein, human; C489984:PRPF4B protein, human
keywords: HER2; HER2, human epidermal growth factor receptor 2; PRP4K; PRP4K, pre-mRNA splicing factor-4 kinase; SAC, spindle assembly checkpoint; TMA, tissue microarray; breast cancer; ovarian cancer; taxane sensitivity