TY - JOUR
T1 - FOXO transcriptional activity is associated with response to chemoradiation in EAC
AU - Creemers, A.
AU - van der Zalm, A. P.
AU - van de Stolpe, A.
AU - Holtzer, L.
AU - Stoffels, M.
AU - Ebbing, E. A.
AU - van Ooijen, H.
AU - van Brussel, A. G. C.
AU - Aussems-Custers, E. M. G.
AU - van Berge Henegouwen, M. I.
AU - Hulshof, M. C. C. M.
AU - Bergman, J. J. G. H. M.
AU - Meijer, S. L.
AU - Bijlsma, M. F.
AU - van Laarhoven, H. W. M.
AU - Hooijer, G. K. J.
N1 - Funding Information: All authors have read the journal’s policy on disclosure of potential conflicts of interest. MB has received research funding from Celgene and has acted as a consultant to Servier. HL has served as a consultant for Celgene, BMS, Lilly, and Nordic, and has received unrestricted research funding from Bayer, BMS, Celgene, Lilly, Merck Serono, MSD, Nordic, Philips and Roche. AS, LH, MS, HO, AB and EAC are employees of Philips. Funding Information: This work was supported by Philips Research and Amsterdam UMC. Publisher Copyright: © 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - In this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (nCRT) resection; (ii) 66 EAC patients with resection and corresponding recurrence. Activity of six key cancer-related signaling pathways was inferred using the Bayesian inference method. When assessing pre- and post-nCRT samples, lower FOXO transcriptional activity was observed in poor nCRT responders compared to good nCRT responders (p = 0.0017). This poor responder profile was preserved in recurrences compared to matched resections (p = 0.0007). PI3K pathway activity, inversely linked with FOXO activity, was higher in CRT poor responder cell lines compared to CRT good responders. Poor CRT responder cell lines could be sensitized to CRT using PI3K inhibitors. To conclude, by using a novel method to measure signaling pathway activity on clinically available material, we identified an association of low FOXO transcriptional activity with poor response to nCRT. Targeting this pathway sensitized cells for nCRT, underlining its feasibility to select appropriate targeted therapies.
AB - In this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (nCRT) resection; (ii) 66 EAC patients with resection and corresponding recurrence. Activity of six key cancer-related signaling pathways was inferred using the Bayesian inference method. When assessing pre- and post-nCRT samples, lower FOXO transcriptional activity was observed in poor nCRT responders compared to good nCRT responders (p = 0.0017). This poor responder profile was preserved in recurrences compared to matched resections (p = 0.0007). PI3K pathway activity, inversely linked with FOXO activity, was higher in CRT poor responder cell lines compared to CRT good responders. Poor CRT responder cell lines could be sensitized to CRT using PI3K inhibitors. To conclude, by using a novel method to measure signaling pathway activity on clinically available material, we identified an association of low FOXO transcriptional activity with poor response to nCRT. Targeting this pathway sensitized cells for nCRT, underlining its feasibility to select appropriate targeted therapies.
KW - Esophageal adenocarcinoma
KW - Neoadjuvant chemoradiation therapy
KW - Pathway analysis
KW - Predictive
UR - http://www.scopus.com/inward/record.url?scp=85128807844&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s12967-022-03376-w
DO - https://doi.org/10.1186/s12967-022-03376-w
M3 - Article
C2 - 35468793
SN - 1479-5876
VL - 20
JO - Journal of translational medicine
JF - Journal of translational medicine
IS - 1
M1 - 183
ER -