β-Catenin Mediates Resistance to PI3K and AKT Inhibitors in Colon Cancer

Elevated PI3K/AKT signaling in tumors increases phosphorylation and cytoplasmic sequestration of the transcription factor forkhead box O3a (FOXO3a), leading to suppression of proapoptotic FOXO3a target genes. Given the high frequency of WNT–β-catenin pathway activation in human colon cancers and the known interaction between FOXO3a and β-catenin, Tenbaum and colleagues studied cross-talk between β-catenin and FOXO3a in colon cancer. Interestingly, nuclear FOXO3a only colocalized with β-catenin in malignant cells, and high levels of nuclear β-catenin and FOXO3a in tumors correlated with advanced disease and shorter survival time. Induced co-expression of nuclear β-catenin and FOXO3a in colon cancer cells led to a complete rescue of FOXO3a-induced apoptosis and increased expression of FOXO3a target genes that affected cellular morphology and contributed to enhanced motility. Consistent with these in vitro findings, injection of colon cancer cells co-expressing nuclear FOXO3a and β-catenin into the intestines of nude mice increased metastasis compared with expression of either protein alone. Treatment with AKT or PI3K inhibitors that induced nuclear localization of FOXO3a also selectively promoted metastasis of tumor xenografts expressing high levels of nuclear β-catenin, further suggesting that nuclear β-catenin and FOXO3a cooperate to drive metastasis and indicating that β-catenin may mediate resistance to these inhibitors. Indeed, nuclear β-catenin conferred dose-dependent resistance to AKT or PI3K inhibitors that could be reversed with a WNT pathway inhibitor. Furthermore, treatment with PI3K or AKT inhibitors only induced apoptosis in sphere cultures and xenografts derived from patients with low nuclear β-catenin concentrations, but had no effect on those derived from patients with high nuclear β-catenin levels. These findings thus suggest that PI3K and AKT inhibitors should not be used in colon cancer patients with high nuclear β-catenin levels and that combined use of WNT/β-catenin and PI3K/AKT inhibitors may be effective in colon cancers.

Tenbaum SP, Ordóñez-Moran P, Puig I, Chicote I, Arqués O, Landolfi S, et al. β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nat Med 2012;18:892–901.

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