RRC ID 58095
Author Kuroda T, Ogiwara H, Sasaki M, Takahashi K, Yoshida H, Kiyokawa T, Sudo K, Tamura K, Kato T, Okamoto A, Kohno T.
Title Therapeutic preferability of gemcitabine for ARID1A-deficient ovarian clear cell carcinoma.
Journal Gynecol Oncol
Abstract OBJECTIVE:Ovarian clear cell carcinoma (OCCC) is often resistant to conventional, standard chemotherapy using cytotoxic drugs. OCCC harbors a unique genomic feature of frequent (approximately 50%) ARID1A deficiency. The present study was performed to investigate standard chemotherapeutic options suitable for ARID1A-deficient OCCC patients.
METHODS:Drugs with selective toxicity to ARID1A-deficient OCCC cells were identified among six cytotoxic drugs used in standard chemotherapy for OCCC by employing multiple ARID1A-knockout cell lines and an OCCC cell line panel. Anti-tumor effects of drug treatment were assessed using a xenograft model. To obtain proof of concept in patients, seven OCCC patients who received single-agent therapy with gemcitabine were identified in a retrospective cohort of 149 OCCC patients. Patient samples and cases were analyzed for association between therapeutic response and ARID1A deficiency.
RESULTS:ARID1A-knockout and ARID1A-deficient OCCC cells had selective sensitivity to gemcitabine. IC50 values for gemcitabine of ARID1A-deficient cells were significantly lower than those of ARID1A-proficient cells (p = 0.0001). Growth of OCCC xenografts with ARID1A deficiency was inhibited by administration of gemcitabine, and gemcitabine treatment effectively induced apoptosis in ARID1A-deficient OCCC cells. Three ARID1A-deficient OCCC patients had significantly longer progression-free survival after gemcitabine treatment than four ARID1A-proficient OCCC patients (p = 0.02). An ARID1A-deficient case that was resistant to multiple cytotoxic drugs, including paclitaxel plus carboplatin in the adjuvant and etoposide plus irinotecan in the first-line treatment, exhibited a dramatic response to gemcitabine in the second-line treatment.
CONCLUSION:ARID1A-deficient OCCC patients could benefit from gemcitabine treatment in clinical settings.
Volume 155(3)
Pages 489-498
Published 2019-12-1
DOI 10.1016/j.ygyno.2019.10.002
PII S0090-8258(19)31559-8
PMID 31604667
MeSH Adenocarcinoma, Clear Cell / drug therapy* Adenocarcinoma, Clear Cell / genetics Adenocarcinoma, Clear Cell / metabolism Adenocarcinoma, Clear Cell / pathology Adult Aged Animals Antimetabolites, Antineoplastic / administration & dosage Antimetabolites, Antineoplastic / pharmacology Apoptosis / drug effects Cell Line, Tumor Deoxycytidine / administration & dosage Deoxycytidine / analogs & derivatives* Deoxycytidine / pharmacology Female Gene Knockout Techniques HCT116 Cells HEK293 Cells Humans Immunohistochemistry Mice Mice, Inbred BALB C Middle Aged Nuclear Proteins / deficiency* Nuclear Proteins / genetics Nuclear Proteins / metabolism Ovarian Neoplasms / drug therapy* Ovarian Neoplasms / genetics Ovarian Neoplasms / metabolism Ovarian Neoplasms / pathology Random Allocation Transcription Factors / deficiency* Transcription Factors / genetics Transcription Factors / metabolism Xenograft Model Antitumor Assays
IF 4.393
Times Cited 2
Human and Animal Cells JHOC-9(RCB2226)