Patient derived organoids confirm that PI3K/AKT signalling is an escape pathway for radioresistance and a target for therapy in rectal cancer.
Barros-Silva, Joao D Tee, Louise El-Asrag, Mohammed E Stodolna, Agata Pickles, Oliver J Stockton, Joanne Bryer, Claire Hoare, Rachel Whalley, Celina M
Barros-Silva, Joao D
Tee, Louise
El-Asrag, Mohammed E
Stodolna, Agata
Pickles, Oliver J
Stockton, Joanne
Bryer, Claire
Hoare, Rachel
Whalley, Celina M
Citations
Altmetric:
Affiliation
Other Contributors
Publication date
2022-07-04
Subject
Collections
Research Projects
Organizational Units
Journal Issue
Abstract
Objectives: Partial or total resistance to preoperative chemoradiotherapy occurs in more than half of locally advanced rectal cancer patients. Several novel or repurposed drugs have been trialled to improve cancer cell sensitivity to radiotherapy, with limited success. We aimed to understand the mechanisms of resistance to chemoradiotherapy in rectal cancer using patient derived organoid models.
Design: To understand the mechanisms underlying this resistance, we compared the pre-treatment transcriptomes of patient-derived organoids (PDO) with measured radiotherapy sensitivity to identify biological pathways involved in radiation resistance coupled with single cell sequencing, genome wide CRISPR-Cas9 and targeted drug screens.
Results: RNA sequencing enrichment analysis revealed upregulation of PI3K/AKT/mTOR and epithelial mesenchymal transition pathway genes in radioresistant PDOs. Single-cell sequencing of pre & post-irradiation PDOs showed mTORC1 and PI3K/AKT upregulation, which was confirmed by a genome-wide CRSIPR-Cas9 knockout screen using irradiated colorectal cancer (CRC) cell lines. We then tested the efficiency of dual PI3K/mTOR inhibitors in improving cancer cell sensitivity to radiotherapy. After irradiation, significant AKT phosphorylation was detected (p=0.027) which was abrogated with dual PI3K/mTOR inhibitors and lead to significant radiosensitisation of the HCT116 cell line and radiation resistant PDO lines.
Conclusions: The PI3K/AKT/mTOR pathway upregulation contributes to radioresistance and its targeted pharmacological inhibition leads to significant radiosensitisation in CRC organoids, making it a potential target for clinical trials.
Citation
Wanigasooriya K, Barros-Silva JD, Tee L, El-Asrag ME, Stodolna A, Pickles OJ, Stockton J, Bryer C, Hoare R, Whalley CM, Tyler R, Sillo T, Yau C, Ismail T, Beggs AD. Patient Derived Organoids Confirm That PI3K/AKT Signalling Is an Escape Pathway for Radioresistance and a Target for Therapy in Rectal Cancer. Front Oncol. 2022 Jul 4;12:920444. doi: 10.3389/fonc.2022.920444
Type
Article