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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/102696
Therapeutic inhibition of PI3K/AKT and WNT/b-catenin pathways in colorectal cancer
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[eng] olorectal cancer (CRC) is a leading cause of death worldwide, especially in the late stages of the disease when relapse and metastasis occur. Despite the improvements achieved recently in terms of treatment and diagnosis, current therapies for advanced CRC are still not curative. Among the new therapeutic strategies evaluated in the clinic, PI3K/AKT signaling pathway inhibitors are widely studied and are promising candidates. However, in the case of CRC, resistance to such drugs is very frequent. Alterations in the Wnt signaling pathway are thought to be one of the earliest steps in the initiation of CRC. This pathway controls the stability of its main effector, b-catenin, which has been shown to interact with FOXO3a, a tumor suppressor controlled by the PI3K/AKT signaling pathway. In this work we studied the molecular crosstalk between both factors and its implications in CRC. We showed that b-catenin is able to induce resistance to FOXO3a-mediated apoptosis by modulating its transcriptional activity. Instead of promoting apoptosis, simultaneous activation of both factors induced cell cycle arrest and imposed a metastatic phenotype. Furthermore, FOXO3a activation by PI3K or AKT inhibitors induced metastasis of tumors with high nuclear b-catenin content. Such activated b-catenin also conferred resistance to these treatments in CRC patient-derived xenografts (PDXs). We proved that inhibition of the Wnt pathway, using tankyrase inhibitors, could reduce nuclear b-catenin amounts and sensitize CRC cells and PDX models to the treatment with PI3K and AKT inhibitors. In accordance, we have shown that nuclear b-catenin could be used as a biomarker of resistance to PI3K/AKT pathway inhibitors while FOXO3a could constitute a biomarker of sensitivity to Wnt/tankyrase inhibitors. Altogether, our results could help improving the molecular selection of CRC patients and their stratification for the treatment with PI3K/AKT and Wnt pathway inhibitors.
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ARQUÉS CASAMITJANA, Oriol. Therapeutic inhibition of PI3K/AKT and WNT/b-catenin pathways in colorectal cancer. [consulta: 6 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/102696]