Table 2 Clinical trials of clear cell carcinoma exploiting ARID1A synthetic lethal interactions

ATR-inhibitor

VX-970

OCCC

ARID1A deficiency results in topoisomerase 2A and cell cycle defects, which cause an increased reliance on ATR checkpoint activity. Therefore, inhibition of ATR triggers premature mitotic entry, genomic instability and apoptosis in ARID1A-loss tumor

In vitro studies, we found that the human OCCC cell line was more sensitive to VX-970 than the ARID1A wild-type OCCC cell line(P < 0.0001) and also exhibited a DNA damage and apoptotic response to ATR-inhibitor exposure. Moreover, in a mouse human OCCC transplantation model, the use of ATR inhibitors significantly inhibited the growth of ARID1A-loss tumors with no significant adverse effects on normal tissues

[43]

ATR-inhibitor + ICB therapy

AZD6738

Durvalumab

Advanced-stage and/or recurrent solid tumors

ART-inhibitors can disrupt DNA repair in tumor cells and thus lead to the release of more tumor cell antibodies

Objective response rate: 17% (2/12)

[44]

ATR-inhibitor + PARP-inhibitor

Ceralasertib

Olaparib

OCCC

ARID1A is involved in the DNA double-strand brink process in tumor cells, similar to the role played by BRCA in tumor cells

On-going

[45]

AURKA-inhibitor

ENMD-2076

OCCC

AURKA acts as an oncogene that can cause tumor cell overriding cell cycle checkpoints by phosphorylate CDC25 Cat Ser198 via PLK1 and activate CDC25C nuclear translocation leading to tumor cells overriding cell cycle checkpoints, and enhancing cell proliferation, and suppressing apoptotic pathways. Loss of ARID1A can upregulate the expression level of AURKA

6- month PFS rate of ARID1A-loss OCCC patients: 33%

6- month PFS rate of ARID1A-wild OCCC patients: 12%

P = 0.023

[46]

Tyrosine kinase inhibitor

Dasatinib

OCCC

Endometrial CCC

Acting on P21 and Rb to cause more ARID1A-loss cells to enter the G1-S cell cycle arres

Inhibiting the growth and division of cancer cells by inhibiting their angiogenesis

Response rate: 3.8% (1/28)

Mean PFS: 2.14 months

[47]

EZH2 inhibitor

GSK126

OCCC

EZH2, as a key component of PCR2, modifies histone H3 on chromatin and wraps it tightly in nucleosomes, making chromatin more compact and thus suppressing gene transcription and expression

Inhibition of EZH2 can lead to upregulation of PIK3IP1 expression, which in turn inhibits PI3K-AKT signaling and contributes to the synthetic lethal interaction between ARID1A and EZH2

ARID1A mutational status correlated with response to the EZH2 inhibitor

The growth rate of ARID1A-loss OCCC cells: 28.4%

The growth rate of ARID1A-wild OCCC cells: 66.0%

P < 0.001

[48]

HDAC2 inhibitor

SAHA

OC

HDAC2 functions as a corepressor of EZH2 and a component of PRC2 to suppress the expression of EZH2/ARID1A target tumor suppressor genes such as PIK3IP1 to inhibit proliferation and promote apoptosis

Compared with ARID1A wild-type cells, the half maximal inhibitory concentration (IC50) of SAHA is significantly lower in ARID1A-mutated cells (P = 0.008)

SAHA treatment significantly reduced the tumor burden (P < 0.001) and the amount of ascites formed (P = 0.009) in mice bearing ARID1A-mutated tumors

[49]

Glutamate-cysteine ligase synthetase catalytic subunit (GCLC) inhibitor

APR246 and PRIMA-1

OC

Controlling cysteine required for glutathione production and causes apoptosis triggered by excess reactive oxygen species

Compared with ARID1A wild-type cancer cells, glutathione is significantly reduced in ARID1A-deficient cancer cells and leads to massive apoptosis (P < 0.001)

[50]

HSF-1 inhibitor

NXP800 (Nuvectis)

OCCC

HSF1(Heat Shock Factor 1), as an ancient stress-inducible transcription factor, plays a key role in the transcriptional activation of the eukaryotic heat shock response and acts as a master transcriptional regulator of proteostasis. The HSF1 pathway has been shown to play a key role in oncogenesis and the hallmark features of malignancy and is important in the initiation and progression of many experimental cancer models

On-going

[51]

Bromodomain and extra terminal (BET) inhibitor

JQ1

iBET762

OCCC

BET inhibitors cause a reduction in the expression of multiple SWI/SNF members including ARID1B, providing a potential explanation for the observed lethal interaction with ARID1A loss

BET inhibitors can inhibit the proliferation of ARID1A mutant OCCC lines significantly (P < 0.001)

ARID1A depletion enhances sensitivity to BET inhibitors (P < 0.001)

[52]