23P - Synthetic lethality by targeting RHEB in ARID1A-mutated luminal breast cancer

Background

The heterogeneous nature of luminal breast cancer alters the patients’ response to the treatment. Despite the proven success of endocrine therapy, not all patients respond, or substantially, those who initially responded might develop endocrine resistance. It is necessary to determine novel anti-cancer agents to be used as a combination with the standard endocrine therapy regimens. Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, are present at a high frequency in advanced ER⁺ breast cancer. Developing synthetic lethality (SL)-based therapeutic strategies for ARID1A-mutated breast cancer holds promise.

Methods

Here we first confirmed the effect of ARID1A knockout on endocrine therapeutic response in ER⁺ breast cancer in vitro. The effect on cell proliferation, viability, apoptosis, and EMT was evaluated. The synthetic lethal partner of ARID1A in breast cancer cell lines was identified using SLIdR (Synthetic Lethal Identification in R), a rank-based statistical method for predicting SL pairs from large-scale perturbation screens, The effect of genetic perturbations of RHEB on cell proliferation, apoptosis, and endocrine therapy response was evaluated in ARID1A-deficient BRCA cells compared to control cells. These results were further confirmed in ARID1A-mutated T47D cells.

Results

In vitro proliferation and viability assays confirmed increased proliferation of ARID1A KO MCF7 cells on endocrine treatment. ARID1A KO cells also promoted EMT. RHEB (Ras Homolog, MTORC1 Binding) was identified as the synthetic lethality pair of ARID1A in breast cancer cell lines. Genetic perturbations of RHEB showed that targeting RHEB selectively inhibit the growth of ARID1A-deficient BRCA cells. Moreover, knockout of RHEB in T47D cells, a breast cancer cell line carrying an ARID1A somatic mutation, significantly impaired cell proliferation, triggers apoptosis and led to susceptibility to endocrine therapy compared to control cells.

Conclusions

This study shows a novel synthetic lethality interaction between ARID1A-RHEB and hypothesizes that the development of small molecule inhibitors of RHEB that selectively inhibits the activation of mTORC1 might represent a novel strategy for treating BRCA with ARID1A loss-of-function mutations.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.