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.
†Women's Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, 3289 Woodburn Road, Annandale, Virginia 22003, United States.
Nicholas W
NW
Bateman
†Women's Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, 3289 Woodburn Road, Annandale, Virginia 22003, United States.
Elizabeth
E
Jaworski
†Women's Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, 3289 Woodburn Road, Annandale, Virginia 22003, United States.
Wei
W
Ao
†Women's Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, 3289 Woodburn Road, Annandale, Virginia 22003, United States.
Guisong
G
Wang
†Women's Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, 3289 Woodburn Road, Annandale, Virginia 22003, United States.
Tracy
T
Litzi
†Women's Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, 3289 Woodburn Road, Annandale, Virginia 22003, United States.|‡Gynecologic Oncology Service, Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, Maryland 20814, United States.
Elizabeth
E
Dubil
†Women's Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, 3289 Woodburn Road, Annandale, Virginia 22003, United States.|‡Gynecologic Oncology Service, Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, Maryland 20814, United States.
Charlotte
C
Marcus
†Women's Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, 3289 Woodburn Road, Annandale, Virginia 22003, United States.
Kelly A
KA
Conrads
†Women's Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, 3289 Woodburn Road, Annandale, Virginia 22003, United States.
Pang-ning
PN
Teng
†Women's Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, 3289 Woodburn Road, Annandale, Virginia 22003, United States.
Brian L
BL
Hood
†Women's Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, 3289 Woodburn Road, Annandale, Virginia 22003, United States.|‡Gynecologic Oncology Service, Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, Maryland 20814, United States.
Neil T
NT
Phippen
†Women's Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, 3289 Woodburn Road, Annandale, Virginia 22003, United States.
Lisa A
LA
Vasicek
§Massey Cancer Center, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia 23298, United States.
William P
WP
McGuire
∥Champions Oncology, Inc., 855 North Wolfe Street, Suite 619, Baltimore, Maryland 21205, United States.
Keren
K
Paz
⊥Otolaryngology-Head and Neck Surgery and Oncology, Johns Hopkins University, 1550 Orleans Street, Baltimore, Maryland 21287, United States.
David
D
Sidransky
†Women's Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, 3289 Woodburn Road, Annandale, Virginia 22003, United States.|‡Gynecologic Oncology Service, Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, Maryland 20814, United States.
Chad A
CA
Hamilton
†Women's Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, 3289 Woodburn Road, Annandale, Virginia 22003, United States.|#Department of Obstetrics and Gynecology, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, Virginia 22042, United States.
G Larry
GL
Maxwell
†Women's Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, 3289 Woodburn Road, Annandale, Virginia 22003, United States.
Kathleen M
KM
Darcy
†Women's Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, 3289 Woodburn Road, Annandale, Virginia 22003, United States.
Thomas P
TP
Conrads
D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D015331:Cohort Studies; D019175:DNA Methylation / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D010051:Ovarian Neoplasms / Q000175:diagnosis*; D017239:Paclitaxel / Q000378:metabolism*; D063868:Patient Outcome Assessment; D011379:Prognosis; D040901:Proteomics / Q000379:methods
D054758:A Kinase Anchor Proteins; C491162:AKAP12 protein, human; D018797:Cell Cycle Proteins; D017239:Paclitaxel
AKAP12; Ovarian cancer; paclitaxel resistance; proteomics; secretome