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.

日本語要旨: