GSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cells

Le Zhang; Lidia Atencia Taboada; Selami Baglamis; Maartje de Kroon; Carolien Elshout; Prashanthi Ramesh; Roxan F C P A Helderman; Arezo Torang; Kate Cameron; Milou S van Driel; Valérie M Wouters; Sanne M van Neerven; Jan Paul Medema

doi:10.1038/s41389-025-00569-y

GSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cells

Oncogenesis. 2025 Jul 13;14(1):25. doi: 10.1038/s41389-025-00569-y.

Authors

Le Zhang^#^{1

2}, Lidia Atencia Taboada^#^{1

2}, Selami Baglamis^{1

2}, Maartje de Kroon^{1

2}, Carolien Elshout^{1

2}, Prashanthi Ramesh^{1

2}, Roxan F C P A Helderman^{1

2}, Arezo Torang^{1

2}, Kate Cameron^{1

2}, Milou S van Driel^{1

2}, Valérie M Wouters^{1

2}, Sanne M van Neerven^{1

3}, Jan Paul Medema^{4

5}

Affiliations

¹ LEXOR, Center of Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
² Oncode institute, Amsterdam, The Netherlands.
³ Wellcome Trust-Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.
⁴ LEXOR, Center of Experimental Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. j.p.medema@amsterdamumc.nl.
⁵ Oncode institute, Amsterdam, The Netherlands. j.p.medema@amsterdamumc.nl.

^# Contributed equally.

PMID: 40651944
DOI: 10.1038/s41389-025-00569-y

Abstract

BCL-XL is a crucial anti-apoptotic protein that supports survival of intestinal cells during the progression and in established colorectal cancer (CRC). While targeting BCL-XL with BH3 mimetics is effective, its significant toxicity highlights the need for alternative approaches. Importantly, the early steps in intestinal transformation are marked by a competition between normal and transformed stem cells in which the mutant cells gain a supercompetitive advantage due to the secretion of WNT inhibitors. Using multiple human and murine CRC models, we revealed that GSK-3 inhibition strongly sensitized to BH3 mimetic-induced killing. As expected, GSK-3 inhibition significantly upregulated the WNT pathway, but also led to marked enhancement of BH3 mimetic-induced apoptosis, as measured by mitochondrial BAX aggregation, Caspase-3 activation and Propidium Iodide exclusion. Furthermore, GSK-3 inhibition provided an advantage to wild-type intestinal organoids in competition with APC-mutant counterparts due to reactivation of the WNT pathway. More strikingly, combining GSK-3 and BCL-XL inhibition profoundly affected the supercompetition APC-mutant intestinal cells exert over the wild-types. In effect, the combination therapy enhanced the competitive fitness of wild-type cells and resulted in the killing of APC-mutant organoids, pointing to a novel combination therapy that can be further exploited in the treatment of adenomas and CRC.