Inhibition of AKT enhances chemotherapy efficacy and synergistically interacts with targeting of the Inhibitor of apoptosis proteins in oesophageal adenocarcinoma

Leanne Stevenson, Lauren Cairns, Xiaodun Li, Sriganesh Jammula, Harriet Taylor, Rosalie Douglas, Niamh McCabe, Gerald Gavory, Xavier Jacq, Rebecca C. Fitzgerald, Richard D. Kennedy, Timothy Harrison, Richard C. Turkington*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

The incidence of oesophageal adenocarcinoma (OAC) has risen six-fold in western countries over the last forty years but survival rates have only marginally improved. Hyperactivation of the PI3K-AKT-mTOR pathway is a common occurrence in OAC, driving cell survival, proliferation and resistance to chemotherapeutic agents. Inhibition of AKT has been explored as a treatment strategy with limited success and current inhibitors have failed to progress through clinical trials. Our study, describes a novel allosteric AKT inhibitor, ALM301, and demonstrates an enhancement of the efficacy of conventional chemotherapy when combined with ALM301 in OAC. Reduced sensitivity to ALM301 is associated with high expression of the Inhibitor of Apoptosis (IAP) family of proteins, particularly XIAP. Combined AKT and IAP inhibition synergistically enhanced OAC cell death and successfully re-sensitized ALM301 and chemotherapy resistant cell lines. A high degree of synergism was also observed in patient-derived OAC organoids indicating the potential clinical relevance of the combination. This study demonstrates the role for dual AKT/IAP inhibition in OAC and provides a strong rationale for the further investigation of this highly efficacious combination strategy.

Original languageEnglish
Article number32121
Number of pages14
JournalScientific Reports
Volume14
DOIs
Publication statusPublished - 30 Dec 2024

Keywords

  • adenocarcinoma - drug therapy - metabolism - pathology
  • antineoplastic Agents - pharmacology
  • apoptosis - drug effects
  • cell line, tumor
  • cell proliferation - drug effects
  • cell survival - drug effects
  • drug resistance, neoplasm - drug effects
  • drug synergism
  • esophageal neoplasms - drug therapy - metabolism - pathology
  • humans
  • inhibitor of apoptosis proteins - metabolism - antagonists & inhibitors
  • proto-oncogene proteins c-akt - metabolism
  • signal transduction - drug effects

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