Therapeutic targeting of ARID1A and PI3K/AKT pathway alterations in cholangiocarcinoma
Supharada Tessiri1,2, Anchalee Techasen1,3, Sarinya Kongpetch3,4
1Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand.
Background:
Genetic alterations in ARID1A were detected at a high frequency in cholangiocarcinoma (CCA). Growing evidence indicates that the loss of ARID1A expression leads to activation of the PI3K/AKT pathway and increasing sensitivity of ARID1A-deficient cells for treatment with the PI3K/AKT inhibitor. Therefore, we investigated the association between genetic alterations of ARID1A and the PI3K/AKT pathway and evaluated the effect of AKT inhibition on ARID1A-deficient CCA cells.
Methods:
Alterations of ARID1A, PI3K/AKT pathway-related genes, clinicopathological data and overall survival of 795 CCA patients were retrieved from cBio Cancer Genomics Portal (cBioPortal) databases. The association between genetic alterations and clinical data were analyzed. The effect of the AKT inhibitor (MK-2206) on ARID1A-deficient CCA cell lines and stable ARID1A-knockdown cell lines was investigated. Cell viability, apoptosis, and expression of AKT signaling were analyzed using an MTT assay, flow cytometry, and Western blots, respectively.
Results:
The analysis of a total of 795 CCA samples revealed that ARID1A alterations significantly co-occurred with mutations of EPHA2 (p < 0.001), PIK3CA (p = 0.047), and LAMA1 (p = 0.024). Among the EPHA2 mutant CCA tumors, 82% of EPHA2 mutant tumors co-occurred with ARID1A truncating mutations. CCA tumors with ARID1A and EPHA2 mutations correlated with better survival compared to tumors with ARID1A mutations alone. We detected that 30% of patients with PIK3CA driver missense mutations harbored ARID1A-truncated mutations and 60% of LAMA1-mutated CCA co-occurred with truncating mutations of ARID1A. Interestingly, ARID1A-deficient CCA cell lines and ARID1A-knockdown CCA cells led to increased sensitivity to treatment with MK-2206 compared to the control. Treatment with MK-2206 induced apoptosis in ARID1A-knockdown KKU-213A and HUCCT1 cell lines and decreased the expression of pAKTS473 and mTOR.
Conclusion:
These findings suggest a dependency of ARID1A-deficient CCA tumors with the activation of the PI3K/AKT-pathway, and that they may be more vulnerable to selective AKT pathway inhibitors which can be used therapeutically.
Insights
ARID1A-deficient cholangiocarcinoma (CCA) shows increased PI3K/AKT pathway activation, making these tumors more sensitive to AKT inhibitors like MK-2206. This suggests a potential therapeutic strategy for this cancer type.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- High frequency of ARID1A genetic alterations in cholangiocarcinoma (CCA).
- Loss of ARID1A expression is linked to PI3K/AKT pathway activation.
- ARID1A-deficient cells exhibit heightened sensitivity to PI3K/AKT inhibitors.
Purpose of the Study:
- To investigate the association between ARID1A alterations and the PI3K/AKT pathway in CCA.
- To evaluate the therapeutic effect of AKT inhibition on ARID1A-deficient CCA cells.
Main Methods:
- Analysis of genetic alterations, clinicopathological data, and survival in 795 CCA patients from cBioPortal.
- In vitro studies using ARID1A-deficient and knockdown CCA cell lines treated with AKT inhibitor MK-2206.
- Assessment of cell viability, apoptosis, and AKT signaling pathway markers (pAKT, mTOR).
Main Results:
- ARID1A alterations co-occurred significantly with mutations in EPHA2, PIK3CA, and LAMA1.
- ARID1A-deficient/knockdown CCA cells showed increased sensitivity to MK-2206, leading to apoptosis and reduced pAKT/mTOR signaling.
- CCA tumors with combined ARID1A and EPHA2 mutations correlated with better survival.
Conclusions:
- ARID1A-deficient CCA tumors are dependent on PI3K/AKT pathway activation.
- These tumors demonstrate vulnerability to selective AKT pathway inhibitors.
- AKT pathway inhibitors represent a potential therapeutic strategy for ARID1A-deficient CCA.
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