Selective vulnerability of ARID1A deficient colon cancer cells to combined radiation and ATR-inhibitor therapy

Abstract

ARID1A is frequently mutated in colorectal cancer (CRC) cells. Loss of ARID1A function compromises DNA damage repair and increases the reliance of tumor cells on ATR-dependent DNA repair pathways. Here, we investigated the effect of ionizing radiation (IR), in combination with ATR inhibitors (ATRi) in CRC cell lines with proficient and deficient ARID1A. The concept of selective vulnerability of ARID1A deficient CRC cells to ATRi was further tested in an ex vivo system by using the ATP-tumor chemosensitivity assay (ATP-TCA) in cells from untreated CRC patients, with and without ARID1A expression. We found selective sensitization upon ATRi treatment as well as after combined treatment with IR (P<0.001), especially in ARID1A deficient CRC cells (P <0.01). Knock-down of ARID1B further increased the selective radiosensitivity effect of ATRi in ARID1A negative cells (P<0.01). Mechanistically, ATRi abrogates the G2 checkpoint (P<0.01) and homologous recombination repair (P<0.01) in ARID1A deficient cells. Most importantly, ex-vivo experiments showed that ATRi had the highest radiosensitizing effect in ARID1A negative cells from CRC patients. Collectively, our results generate pre-clinical and clinical mechanistic rationale for assessing ARID1A defects as a biomarker for ATR inhibitor response as a single agent, or in a synthetic lethal approach in combination with IR.

Comparison of the Effectiveness of Radiotherapy with 3D-CRT, IMRT, VMAT and PT for Newly Diagnosed Glioblastoma: A Bayesian Network Meta-Analysis

“…RT technology has advanced dramatically over the last few decades [25,26]. In contrast to traditional 2D treatment strategies, 3DCRT has greatly improved dose distribution and, subsequently, local control for prostate cancer and other tumor entities [6,[26][27][28][29]. To date, 3DCRT has been the most available RT planning modality worldwide.…”

Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes

“…Also, in tumors with high levels of microsatellite instability (MSI-H) that are characterized by decreased levels of WRN helicase, it has been shown that ATR inhibition may potentiate tumor cell death [ 113 ]. MSI-H tumors may also present mutations in the ARID1A chromatin remodeling protein that plays a substantial role in DNA repair [ 114 ]. ARID1A loss of function is quite common, mostly among gynecological cancers, and renders the ATR pathway indispensable for ARID1A-deficient cells, as demonstrated in vitro and ex vivo in colorectal cancer (CRC) cells [ 114 , 115 ].…”

“…MSI-H tumors may also present mutations in the ARID1A chromatin remodeling protein that plays a substantial role in DNA repair [ 114 ]. ARID1A loss of function is quite common, mostly among gynecological cancers, and renders the ATR pathway indispensable for ARID1A-deficient cells, as demonstrated in vitro and ex vivo in colorectal cancer (CRC) cells [ 114 , 115 ]. Mechanistically, ARID1A-deficient cells are characterized by loss of the G2/M cell cycle checkpoint and impaired homologous recombination.…”

“…Mechanistically, ARID1A-deficient cells are characterized by loss of the G2/M cell cycle checkpoint and impaired homologous recombination. When treated with ATR inhibitors, genomic instability is induced, leading to cell death [ 114 , 115 , 116 ].…”

Therapeutic targeting of ARID1A-deficient cancer cells with RITA (Reactivating p53 and inducing tumor apoptosis)

“…Recent studies have shown that ARID1A has a synthetic lethal interaction with several cancer-associated proteins, including EZH2 [ 16 ], HDAC6 [ 17 ], GCLC [ 18 ], and AURKA [ 19 ]. Inhibiting these synthetic lethality targets results in selective vulnerabilities in ARID1A mutant OCCC [ 20 ], CRC [ 21 ], and breast cancer cells [ 22 ]. These studies demonstrate that synthetic lethal targeting of ARID1A is a promising approach for the development of novel cancer-targeted therapies.…”