TY - JOUR
T1 - Circulating extracellular vesicles protein expression for early prediction of platinum-resistance in high-grade serous ovarian cancer
AU - Wagner, Vincent
AU - Morton, Molly
AU - Dorayappan, Kalpana Deepa Priya
AU - Gonzalez, Anna
AU - Yu, Lianbo
AU - Sakaue, Takahiko
AU - Conrads, Thomas
AU - Maxwell, G. Larry
AU - Cosgrove, Casey
AU - Backes, Floor
AU - Wang, Qi En
AU - Cohn, David E.
AU - O’Malley, David M.
AU - Selvendiran, Karuppaiyah
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025
Y1 - 2025
N2 - Platinum resistance in high-grade serous ovarian carcinoma (HGSOC) portends a poor prognosis. Although initial platinum-based chemotherapy response rates are high, 15-20% of patients demonstrate primary resistance to platinum therapy and almost all patients will develop platinum resistance in the recurrent setting. No predictive or diagnostic biomarkers have been utilized specific to platinum resistance. This study aimed to identify candidate biomarkers for platinum resistance in HGSOC using an extracellular vesicle (EV) based approach. We found differentially expressed and distinct EV proteins, namely TMEM205 and CFH, in patients with platinum-resistant (PR) HGSOC compared to those of platinum-sensitive (PS) patients, utilizing liquid chromatography-tandem mass spectrometry (LC-MS/MS). Expression of these EV proteins were validated in patient-derived PR cell lines as well as in clinically relevant mouse models of HGSOC post-platinum therapy. We corroborated these findings using serum samples from patients with PS and PR-HGSOC. Both EV CFH and EV TMEM205 exhibited excellent diagnostic capability for PR as noted by receiver operating characteristic curves with area under the curve values of 0.95 and 0.84, respectively. The high diagnostic performance of TMEM205 and CFH within EVs compared to the relatively poor performance of conventional serum proteins such as Ca125 suggests their robust potential as non-invasive biomarkers for detecting platinum resistance in HGSOC. Furthermore, the ROC curve for the combined biomarker demonstrated excellent diagnostic performance, with an AUC of 0.973, a true positive rate (TPR) of 0.938, and a false positive rate (FPR) of 0.062. Incorporating this multi-protein biomarker panel alongside established biomarkers further enhances diagnostic accuracy. Serum EV CFH and TMEM205 are promising biomarkers for early detection of platinum resistance in HGSOC and may highlight underlying chemoresistance mechanisms, offering potential future therapeutic targets.
AB - Platinum resistance in high-grade serous ovarian carcinoma (HGSOC) portends a poor prognosis. Although initial platinum-based chemotherapy response rates are high, 15-20% of patients demonstrate primary resistance to platinum therapy and almost all patients will develop platinum resistance in the recurrent setting. No predictive or diagnostic biomarkers have been utilized specific to platinum resistance. This study aimed to identify candidate biomarkers for platinum resistance in HGSOC using an extracellular vesicle (EV) based approach. We found differentially expressed and distinct EV proteins, namely TMEM205 and CFH, in patients with platinum-resistant (PR) HGSOC compared to those of platinum-sensitive (PS) patients, utilizing liquid chromatography-tandem mass spectrometry (LC-MS/MS). Expression of these EV proteins were validated in patient-derived PR cell lines as well as in clinically relevant mouse models of HGSOC post-platinum therapy. We corroborated these findings using serum samples from patients with PS and PR-HGSOC. Both EV CFH and EV TMEM205 exhibited excellent diagnostic capability for PR as noted by receiver operating characteristic curves with area under the curve values of 0.95 and 0.84, respectively. The high diagnostic performance of TMEM205 and CFH within EVs compared to the relatively poor performance of conventional serum proteins such as Ca125 suggests their robust potential as non-invasive biomarkers for detecting platinum resistance in HGSOC. Furthermore, the ROC curve for the combined biomarker demonstrated excellent diagnostic performance, with an AUC of 0.973, a true positive rate (TPR) of 0.938, and a false positive rate (FPR) of 0.062. Incorporating this multi-protein biomarker panel alongside established biomarkers further enhances diagnostic accuracy. Serum EV CFH and TMEM205 are promising biomarkers for early detection of platinum resistance in HGSOC and may highlight underlying chemoresistance mechanisms, offering potential future therapeutic targets.
UR - http://www.scopus.com/inward/record.url?scp=105002219052&partnerID=8YFLogxK
U2 - 10.1038/s41388-025-03382-4
DO - 10.1038/s41388-025-03382-4
M3 - Article
AN - SCOPUS:105002219052
SN - 0950-9232
JO - Oncogene
JF - Oncogene
M1 - 1093
ER -