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ARID1A loss sensitizes colorectal cancer cells to floxuridine
Cheng Xiang1, Zhen Wang2, Yingnan Yu2
1Guangdong Provincial key laboratory of Gastroenterology, Department of Gastroenterology, Nanfang hospital, Southern Medical University, Guangzhou, 510515, China; Comprehensive Medical Treatment Ward, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Abstract:
The loss-of-function mutation of AT-rich interactive domain 1A (ARID1A) frequently occurs in various types of cancer, making it a promising therapeutic target. In the present study, we performed a screening of an FDA-approved drug library in ARID1A isogenic colorectal cancer (CRC) cells and discovered that ARID1A loss sensitizes CRC cells to floxuridine (FUDR), an antineoplastic agent used for treating hepatic metastases from CRC, both in vivo and in vitro. As a pyrimidine analogue, FUDR induces DNA damage by inhibiting thymidylate synthase (TS) activity. ARID1A, as a regulator of DNA damage repair, when lost, exacerbates FUDR-induced DNA damage, leading to increased cell apoptosis. Specifically, ARID1A deficiency impairs DNA damage repair by downregulating Chk2 phosphorylation, thereby sensitizing cancer cells to FUDR. Notably, we found that FUDR exhibited increased sensitivity in ARID1A-deficient cells compared to 5-fluorouracil (5-FU), a commonly used anticancer drug for CRC. This suggests that FUDR is superior to 5-FU in treating ARID1A-deficient CRC. In conclusion, ARID1A loss significantly heightens sensitivity to FUDR by promoting FUDR-induced DNA damage in CRC. These findings offer a novel therapeutic approach for the treatment of CRC characterized by ARID1A loss-of-function mutations.
Insights
Loss of ARID1A in colorectal cancer (CRC) sensitizes cells to floxuridine (FUDR). ARID1A deficiency impairs DNA repair, enhancing FUDR
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Loss-of-function mutations in AT-rich interactive domain 1A (ARID1A) are common in various cancers.
- ARID1A's role in DNA damage repair suggests its potential as a therapeutic target.
- Colorectal cancer (CRC) with ARID1A mutations presents a challenge for effective treatment.
Purpose of the Study:
- To identify therapeutic vulnerabilities associated with ARID1A loss in CRC.
- To evaluate the efficacy of FDA-approved drugs in ARID1A-deficient CRC models.
- To explore the mechanisms underlying ARID1A's influence on drug sensitivity.
Main Methods:
- Screening of an FDA-approved drug library in ARID1A isogenic CRC cell lines.
- In vitro and in vivo assessments of drug efficacy and cellular response.
- Analysis of DNA damage repair pathways, including Chk2 phosphorylation.
Main Results:
- ARID1A loss sensitizes CRC cells to floxuridine (FUDR).
- FUDR, a thymidylate synthase inhibitor, induces DNA damage that is exacerbated by ARID1A deficiency.
- ARID1A loss impairs DNA damage repair by downregulating Chk2 phosphorylation, increasing apoptosis.
- FUDR demonstrated superior efficacy compared to 5-fluorouracil (5-FU) in ARID1A-deficient CRC models.
Conclusions:
- ARID1A loss significantly enhances sensitivity to FUDR in CRC by promoting DNA damage.
- FUDR represents a promising therapeutic agent for CRC patients with ARID1A loss-of-function mutations.
- These findings introduce a novel therapeutic strategy targeting ARID1A-deficient CRC.
