Type

Journal Article

Authors

Markus Rehm
Daniel b Longley
Jochen HM Prehn
Carla L O'Connor
Ruth E Mooney
Frank A Lincoln
Christian T Hellwig
Manuela Salvucci
Nyree Crawford

Subjects

Biochemistry

Topics
cell death signal transduction drug resistance colon cancer colorectal cancer crc cancer chemotherapy protein expression cancer treatment

Simulating and predicting cellular and in vivo responses of colon cancer to combined treatment with chemotherapy and IAP antagonist Birinapant/TL32711. (2017)

Abstract Apoptosis resistance contributes to treatment failure in colorectal cancer (CRC). New treatments that reinstate apoptosis competency have potential to improve patient outcome but require predictive biomarkers to target them to responsive patient populations. Inhibitor of apoptosis proteins (IAPs) suppress apoptosis, contributing to drug resistance; IAP antagonists such as TL32711 have therefore been developed. We developed a systems biology approach for predicting response of CRC cells to chemotherapy and TL32711 combinations in vitro and in vivo. CRC cells responded poorly to TL32711 monotherapy in vitro; however, co-treatment with 5-fluorouracil (5-FU) and oxaliplatin enhanced TL32711-induced apoptosis. Notably, cells from genetically identical populations responded highly heterogeneously, with caspases being activated both upstream and downstream of mitochondrial outer membrane permeabilisation (MOMP). These data, combined with quantities of key apoptosis regulators were sufficient to replicate in vitro cell death profiles by mathematical modelling. In vivo, apoptosis protein expression was significantly altered, and mathematical modelling for these conditions predicted higher apoptosis resistance that could nevertheless be overcome by combination of chemotherapy and TL32711. Subsequent experimental observations agreed with these predictions, and the observed effects on tumour growth inhibition correlated robustly with apoptosis competency. We therefore obtained insights into intracellular signal transduction kinetics and their population-based heterogeneities for chemotherapy/TL32711 combinations and provide proof-of-concept that mathematical modelling of apoptosis competency can simulate and predict responsiveness in vivo. Being able to predict response to IAP antagonist-based treatments on the background of cell-to-cell heterogeneities in the future might assist in improving treatment stratification approaches for these emerging apoptosis-targeting agents.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Markus Rehm, Daniel b Longley, Jochen HM Prehn, Carla L O'Connor, Ruth E Mooney, Frank A Lincoln, Christian T Hellwig, Manuela Salvucci, Nyree Crawford

Experts in our system

1
Markus Rehm
Royal College of Surgeons in Ireland
Total Publications: 55
 
2
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
3
Carla L O'Connor
Royal College of Surgeons in Ireland
Total Publications: 3
 
4
Frank A Lincoln
Royal College of Surgeons in Ireland
Total Publications: 3
 
5
Christian T Hellwig
Royal College of Surgeons in Ireland
Total Publications: 11
 
6
Manuela Salvucci
Royal College of Surgeons in Ireland