Evaluating the efficacy of PARP inhibitor in ARID1A-deficient colorectal cancer: A ex vivo study.

Abstract

ARID1A mutations are a common occurrence in colorectal cancer (CRC) cells, but clinical therapeutic options targeting this anomaly remain unavailable. The loss of ARID1A functionality compromises DNA damage repair processes, potentially causing cancer cells to rely more heavily on PARP-dependent DNA repair pathways to preserve genomic integrity, thereby making them susceptible to PARP inhibitor (PARPi) therapy. To evaluate the suitability of PARPi treatment for CRC patients with ARID1A sufficiency (ARID1A+) and ARID1A deficiency (ARID1A-), our study enrolled 80 patients who had undergone surgical treatment for primary CRC. Surgical specimens underwent immunohistochemical examination to assess ARID1A protein expression. The study explored correlations between ARID1A expression loss and clinicopathological characteristics. Moreover, primary CRC cells were isolated through enzymatic digestion and validated using the colorectal carcinoma marker CK20. Subsequently, PARPi sensitivity was investigated in untreated ARID1A+ and ARID1A- CRC patients using an ATP-tumor chemosensitivity assay (ATP-TCA). Additionally, we confirmed the efficacy of PARPi in these primary CRC cells through clone formation and assessed its impact on cell cycle dynamics, apoptosis, and DNA damage repair signaling pathways using immunofluorescence and flow cytometry. The results demonstrated that the ARID1A- group displayed greater sensitivity to PARPi compared to the ARID1A+ group. PARPi treatment led to increased tumor cell death in the ARID1A- group. Mechanistically, ARID1A deficiency resulted in cell cycle abnormalities, particularly G2/M phase arrest, which was further exacerbated by PARPi treatment. Furthermore, PARPi treatment significantly increased the number of RAD51 foci in ARID1A- cell lines. In conclusion, our study highlights the potential of PARPi as an effective therapeutic option for ARID1A- CRC patients.