Crosstalk between PI3K/AKT/mTOR and WNT/β-Catenin signaling in GBM - Could combination therapy checkmate the collusion?

Abstract

Glioblastoma multiforme is one of the calamitous primary glial brain tumors with extensive heterogeneity at cellular and molecular levels. While maximal surgical resection trailed by radio and chemotherapy employing temozolomide remains the gold-standard treatment for malignant glioma patients, the overall prognosis remains dismal and there exists an unmet need for effective therapeutic strategies. In this context, we hypothesize that proper understanding of signaling pathways responsible for glioblastoma multiforme proliferation would be the first trump card while searching for novel targeted therapies. Among the pathways aberrantly activated, PI3K/AKT/mTOR is the most significant pathway, that is clinically implicated in malignancies such as high-grade glioma. Further, the WNT/β-Catenin cascade is well-implicated in several malignancies, while its role in regulating glioma pathogenesis has only emerged recently. Nevertheless, oncogenic activation of both these pathways is a frequent event in malignant glioma that facilitates tumor proliferation, stemness and chemo-resistance. Recently, it has been reported that the cross-talk of PI3K/AKT/mTOR pathway with multiple signaling pathways could promote glioma progression and reduce the sensitivity of glioma cells to the standard therapy. However, very few studies had focused on the relationship between PI3K/AKT/mTOR and WNT/β-Catenin pathways in glioblastoma multiforme. Interestingly, in homeostatic and pathologic circumstances, both these pathways depict fine modulation and are connected at multiple levels by upstream and downstream effectors. Thus, gaining deep insights on the collusion between these pathways would help in discovering unique therapeutic targets for glioblastoma multiforme management. Hence, the current review aims to address, "the importance of inter-play between PI3K/AKT/mTOR and WNT/β-Catenin pathways", and put forward, "the possibility of combinatorially targeting them", for glioblastoma multiforme treatment enhancement.

Keywords: Combination therapy; Cross-talk; Glioblastoma multiforme; PI3K/AKT/mTOR signaling; WNT/β-Catenin signaling.