Notch signaling in female cancers: a multifaceted node to overcome drug resistance

Abstract

Drug resistance is one of the main challenges in cancer therapy, including in the treatment of female-specific malignancies, which account for more than 60% of cancer cases among women. Therefore, elucidating the underlying molecular mechanisms is an urgent need in gynecological cancers to foster novel therapeutic approaches. Notably, Notch signaling, including either receptors or ligands, has emerged as a promising candidate given its multifaceted role in almost all of the hallmarks of cancer. Concerning the connection between Notch pathway and drug resistance in the afore-mentioned tumor contexts, several studies focused on the Notch-dependent regulation of the cancer stem cell (CSC) subpopulation or the induction of the epithelial-to-mesenchymal transition (EMT), both features implicated in either intrinsic or acquired resistance. Indeed, the present review provides an up-to-date overview of the published results on Notch signaling and EMT- or CSC-driven drug resistance. Moreover, other drug resistance-related mechanisms are examined such as the involvement of the Notch pathway in drug efflux and tumor microenvironment. Collectively, there is a long way to go before every facet will be fully understood; nevertheless, some small pieces are falling neatly into place. Overall, the main aim of this review is to provide strong evidence in support of Notch signaling inhibition as an effective strategy to evade or reverse resistance in female-specific cancers.

Keywords: Notch signaling; cancer stem cells; drug efflux; drug resistance; epithelial-to-mesenchymal transition; female-specific cancers; tumor microenvironment.

Figure 1

Notch-driven drug resistance mechanisms. The cartoon schematically depicts the involvement of Notch signaling in several drug resistance mechanisms [CSCs (cancer stem cells), drug efflux, EMT (epithelial-to-mesenchymal transition), and TME (tumor microenvironment)].

Figure 2

The canonical Notch signaling pathway. In the signal-receiving cell, the Notch receptor precursor is cleaved (S1) by Furin-like convertase in the Golgi compartment, thereby producing Notch extracellular domain (NECD) and Notch transmembrane region (NTM). Upon ligand binding (DLL/JAGGED) expressed on signal-sending cell, NTM is cleaved (S2) by ADAM, resulting in Notch extracellular truncated intermediate (NEXT) exposition to γ-secretase complex cleavage (S3). S3 cleavage allows the release of Notch intracellular domain (NICD), which translocates to the nucleus and interacts with transcriptional regulators (MAML and CSL) to activate the Notch target genes (ON).