Positioning of proteasome inhibitors in therapy of solid malignancies

Abstract

Targeting of the protein degradation pathway, in particular, the ubiquitin-proteasome system, has emerged as an attractive novel cancer chemotherapeutic modality. Although proteasome inhibitors have been most successfully applied in the treatment of hematological malignancies, they also received continuing interest for the treatment of solid tumors. In this review, we summarize the current positioning of proteasome inhibitors in the treatment of common solid malignancies (e.g., lung, colon, pancreas, breast, and head and neck cancer), addressing topics of their mechanism(s) of action, predictive factors and molecular mechanisms of resistance.

Keywords: Bortezomib; Carfilzomib; Drug resistance; Proteasome inhibitors; Solid tumors.

Fig. 1

The UPS-system. Ubiquitin (Ub) is activated by the activating enzyme E1, Ub is then transferred to the conjugating enzyme E2. The ligase E3 enzyme attaches Ub to the target protein (substrate) and a substrate with at least four Ub moieties is then recognized by the proteasome for degradation. The 19S cap of the proteasome removes the Ub moieties after which the substrate is degraded in the 20S into smaller peptides

Fig. 2

An overview of PI-resistance in solid tumors: 1 upregulation of proteasome activity and increased subunit gene expression, 2 proteasome β5-subunit mutations, 3 protective autophagy, 4 apoptosis-mediated resistance due to an altered Mcl-1/Noxa balance, 5 elevated levels of Pgp resulting in an enhanced CFZ efflux, and 6 KRAS mutations associated with reprogramming metabolic pathways