Reference - Detail
|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.|
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.
|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|
|Human and Animal Cells||JHOC-9(RCB2226)|