Therapeutic targeting of ARID1A and PI3K/AKT pathway alterations in cholangiocarcinoma

PeerJ. 2022 Jan 13:10:e12750. doi: 10.7717/peerj.12750. eCollection 2022.

Abstract

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.

Keywords: AKT inhibitor; BAF250a; Biliary tract cancer; Phosphatidylinositol-3-kinase; Protein kinase B.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bile Duct Neoplasms* / drug therapy
  • Bile Ducts, Intrahepatic / metabolism
  • Cholangiocarcinoma* / drug therapy
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • DNA-Binding Proteins / genetics
  • Humans
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphoinositide-3 Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / metabolism
  • Proto-Oncogene Proteins c-akt
  • Transcription Factors / genetics

Substances

  • Proto-Oncogene Proteins c-akt
  • Phosphatidylinositol 3-Kinases
  • Protein Kinase Inhibitors
  • Class I Phosphatidylinositol 3-Kinases
  • Phosphoinositide-3 Kinase Inhibitors
  • ARID1A protein, human
  • DNA-Binding Proteins
  • Transcription Factors

Associated data

  • figshare/10.6084/m9.figshare.16974859

Grants and funding

This work was financially supported by Centre for Research and Development of Medical Diagnostic Laboratories (CMDL), Faculty of Associated Medical Sciences, Khon Kaen University, and the Thailand Research Fund (MRG6280073). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.