Inhibition of AKT enhances chemotherapy efficacy and synergistically interacts with targeting of the Inhibitor of apoptosis proteins in oesophageal adenocarcinoma
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 resistan...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-12-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-83912-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841559481168691200 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Leanne Stevenson |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-fef048df10404b758cee606c430aea71 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-fef048df10404b758cee606c430aea712025-01-05T12:28:17ZengNature PortfolioScientific Reports2045-23222024-12-0114111410.1038/s41598-024-83912-4Inhibition of AKT enhances chemotherapy efficacy and synergistically interacts with targeting of the Inhibitor of apoptosis proteins in oesophageal adenocarcinomaLeanne Stevenson0Lauren Cairns1Xiaodun Li2Sriganesh Jammula3Harriet Taylor4Rosalie Douglas5Niamh McCabe6Gerald Gavory7Xavier Jacq8Rebecca C. Fitzgerald9Richard D. Kennedy10Timothy Harrison11Richard C. Turkington12Patrick G Johnston Centre for Cancer Research, Queen’s University BelfastPatrick G Johnston Centre for Cancer Research, Queen’s University BelfastMRC Cancer Unit, Hutchison/MRC Research Centre, University of CambridgeMRC Cancer Unit, Hutchison/MRC Research Centre, University of CambridgeMRC Cancer Unit, Hutchison/MRC Research Centre, University of CambridgePatrick G Johnston Centre for Cancer Research, Queen’s University BelfastPatrick G Johnston Centre for Cancer Research, Queen’s University BelfastAlmac Discovery LtdAlmac Discovery LtdMRC Cancer Unit, Hutchison/MRC Research Centre, University of CambridgeAlmac Diagnostics LtdAlmac Discovery LtdPatrick G Johnston Centre for Cancer Research, Queen’s University BelfastAbstract 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.https://doi.org/10.1038/s41598-024-83912-4 |
| spellingShingle | 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 Inhibition of AKT enhances chemotherapy efficacy and synergistically interacts with targeting of the Inhibitor of apoptosis proteins in oesophageal adenocarcinoma Scientific Reports |
| title | Inhibition of AKT enhances chemotherapy efficacy and synergistically interacts with targeting of the Inhibitor of apoptosis proteins in oesophageal adenocarcinoma |
| title_full | Inhibition of AKT enhances chemotherapy efficacy and synergistically interacts with targeting of the Inhibitor of apoptosis proteins in oesophageal adenocarcinoma |
| title_fullStr | Inhibition of AKT enhances chemotherapy efficacy and synergistically interacts with targeting of the Inhibitor of apoptosis proteins in oesophageal adenocarcinoma |
| title_full_unstemmed | Inhibition of AKT enhances chemotherapy efficacy and synergistically interacts with targeting of the Inhibitor of apoptosis proteins in oesophageal adenocarcinoma |
| title_short | Inhibition of AKT enhances chemotherapy efficacy and synergistically interacts with targeting of the Inhibitor of apoptosis proteins in oesophageal adenocarcinoma |
| title_sort | inhibition of akt enhances chemotherapy efficacy and synergistically interacts with targeting of the inhibitor of apoptosis proteins in oesophageal adenocarcinoma |
| url | https://doi.org/10.1038/s41598-024-83912-4 |
| work_keys_str_mv | AT leannestevenson inhibitionofaktenhanceschemotherapyefficacyandsynergisticallyinteractswithtargetingoftheinhibitorofapoptosisproteinsinoesophagealadenocarcinoma AT laurencairns inhibitionofaktenhanceschemotherapyefficacyandsynergisticallyinteractswithtargetingoftheinhibitorofapoptosisproteinsinoesophagealadenocarcinoma AT xiaodunli inhibitionofaktenhanceschemotherapyefficacyandsynergisticallyinteractswithtargetingoftheinhibitorofapoptosisproteinsinoesophagealadenocarcinoma AT sriganeshjammula inhibitionofaktenhanceschemotherapyefficacyandsynergisticallyinteractswithtargetingoftheinhibitorofapoptosisproteinsinoesophagealadenocarcinoma AT harriettaylor inhibitionofaktenhanceschemotherapyefficacyandsynergisticallyinteractswithtargetingoftheinhibitorofapoptosisproteinsinoesophagealadenocarcinoma AT rosaliedouglas inhibitionofaktenhanceschemotherapyefficacyandsynergisticallyinteractswithtargetingoftheinhibitorofapoptosisproteinsinoesophagealadenocarcinoma AT niamhmccabe inhibitionofaktenhanceschemotherapyefficacyandsynergisticallyinteractswithtargetingoftheinhibitorofapoptosisproteinsinoesophagealadenocarcinoma AT geraldgavory inhibitionofaktenhanceschemotherapyefficacyandsynergisticallyinteractswithtargetingoftheinhibitorofapoptosisproteinsinoesophagealadenocarcinoma AT xavierjacq inhibitionofaktenhanceschemotherapyefficacyandsynergisticallyinteractswithtargetingoftheinhibitorofapoptosisproteinsinoesophagealadenocarcinoma AT rebeccacfitzgerald inhibitionofaktenhanceschemotherapyefficacyandsynergisticallyinteractswithtargetingoftheinhibitorofapoptosisproteinsinoesophagealadenocarcinoma AT richarddkennedy inhibitionofaktenhanceschemotherapyefficacyandsynergisticallyinteractswithtargetingoftheinhibitorofapoptosisproteinsinoesophagealadenocarcinoma AT timothyharrison inhibitionofaktenhanceschemotherapyefficacyandsynergisticallyinteractswithtargetingoftheinhibitorofapoptosisproteinsinoesophagealadenocarcinoma AT richardcturkington inhibitionofaktenhanceschemotherapyefficacyandsynergisticallyinteractswithtargetingoftheinhibitorofapoptosisproteinsinoesophagealadenocarcinoma |