Extracellular inhibitors can attenuate tumorigenic Wnt pathway activity in adenomatous polyposis coli mutants: Predictions of a validated mathematical model

Abstract

BackgroundDespite considerable investigational efforts, no method to overcome the pathogenesis caused by loss of function (LoF) mutations in tumor suppressor genes has been successfully translated to the clinic. The most frequent LoF mutation in human cancers is Adenomatous polyposis coli (APC), causing aberrant activation of the Wnt pathway. In nearly all colon cancer tumors, the APC protein is truncated, but still retains partial binding abilities.Objective & methodsHere, we tested the hypothesis that extracellular inhibitors of the Wnt pathway, although acting upstream of the APC mutation, can restore normal levels of pathway activity in colon cancer cells. To this end, we developed and simulated a mathematical model for the Wnt pathway in different APC mutants, with or without the effects of the extracellular inhibitors, Secreted Frizzled-Related Protein1 (sFRP1) and Dickhopf1 (Dkk1). We compared our model predictions to experimental data in the literature.ResultsOur model accurately predicts T-cell factor (TCF) activity in mutant cells that vary in APC mutation. Model simulations suggest that both sFRP1 and DKK1 can reduce TCF activity in APC1638N/1572T and Apcmin/min mutants, but restoration of normal activity levels is possible only in the former. When applied in combination, synergism between the two inhibitors can reduce their effective doses to one-fourth of the doses required under single inhibitor application. Overall, re-establishment of normal Wnt pathway activity is predicted for every APC mutant in whom TCF activity is increased by up to 11 fold.ConclusionsOur work suggests that extracellular inhibitors can effectively restore normal Wnt pathway activity in APC-truncated cancer cells, even though these LoF mutations occur downstream of the inhibitory action. The insufficient activity of the truncated APC can be quantitatively balanced by the upstream intervention. This new concept of upstream intervention to control the effects of downstream mutations may be considered also for other partial LoF mutations in other signaling pathways.

IC-2 Suppresses Proliferation and Induces Apoptosis of Bladder Cancer Cells via the Wnt/β-Catenin Pathway

“…The abundance and nuclear location of β-catenin are critical in Wnt signaling pathways activation [ 19 ]. The persistent existence of TCF-β-catenin complex in nuclei is a common feature of cancer [ 20 ]. IC-2, a derivative of ICG-001, is a novel identified small molecular inhibitor targeting Wnt signaling pathway [ 21 ].…”

Gain and loss of function mutations in biological chemical reaction networks: a mathematical model with application to colorectal cancer cells

“…Specifically, we consider two particular classes of mutations, namely LoF and GoF mutations, that are commonly observed in cancer cells (Hochman et al. 2017 ; Lemieux et al. 2015 ; Levine 2019 ; Levine et al.…”

“…Here we are concerned with effects induced by mutations on species concentrations in the CRN. Specifically, we consider two particular classes of mutations, namely LoF and GoF mutations, that are commonly observed in cancer cells (Hochman et al 2017;Lemieux et al 2015;Levine 2019;Levine et al 2019).…”

Gain and Loss of Function mutations in biological chemical reaction networks: a mathematical model with application to colorectal cancer cells

“…Here we are concerned with effects induced by mutations on species concentrations in the CRN. Specifically, we consider LoF and GoF mutations that are commonly observed in cancer cells (Hochman et al, 2017;Lemieux et al, 2015;Levine, 2019;Levine et al, 2019).…”