Elevated AKAP12 in Paclitaxel-Resistant Serous Ovarian Cancer Cells Is Prognostic and Predictive of Poor Survival in Patients

A majority
of high-grade (HG) serous ovarian cancer (SOC) patients
develop resistant disease despite high initial response rates to platinum/paclitaxel-based
chemotherapy. We identified shed/secreted proteins in preclinical
models of paclitaxel-resistant human HGSOC models and correlated these
candidate proteins with patient outcomes using public data from HGSOC
patients. Proteomic analyses of a HGSOC cell line secretome was compared
to those from a syngeneic paclitaxel-resistant variant and from a
line established from an intrinsically chemorefractory HGSOC patient.
Associations between the identified candidate proteins and patient
outcome were assessed in a discovery cohort of 545 patients and two
validation cohorts totaling 795 independent SOC patients. Among the
81 differentially abundant proteins identified (q < 0.05) from paclitaxel-sensitive vs -resistant HGSOC cell secretomes,
AKAP12 was verified to be elevated in all models of paclitaxel-resistant
HGSOC. Furthermore, elevated AKAP12 transcript expression was associated
with worse progression-free and overall survival. Associations with
outcome were observed in three independent cohorts and remained significant
after adjusted multivariate modeling. We further provide evidence
to support that differential gene methylation status is associated
with elevated expression of AKAP12 in taxol-resistant ovarian cancer
cells and ovarian cancer patient subsets. Elevated expression and
shedding/secretion of AKAP12 is characteristic of paclitaxel-resistant
HGSOC cells, and elevated AKAP12 transcript expression is a poor prognostic
and predictive marker for progression-free and overall survival in
SOC patients.