The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

Abstract

Many targeted therapies against cancer are aimed at inhibiting the enzymatic activity of kinases. Thus far, this approach has undoubtedly yielded significant clinical improvements, but has only rarely achieved cures. Other drugs, which selectively elicit proteasome-dependent degradation of oncoproteins, induce the loss of cancer cell self-renewal and promote cell differentiation and/or apoptosis. In acute promyelocytic leukemia, the cooperative degradation of PML/RARA by arsenic and retinoic acid cures most patients. In this condition and others, drug-induced proteolysis of oncoproteins is feasible and underlies improved clinical outcome. Several transcription factors, nuclear receptors, or fusion proteins driving cancer growth could be candidates for proteolysis-based drug-discovery programs. Summary: Some cancer therapies may degrade oncoproteins. Loss of the driver oncoprotein is associated with loss of cancer cell self-renewal. Leukemia- or sarcoma-associated fusion proteins are the best candidates for small-molecule screens aimed at initiating oncoprotein degradation. Cancer Discovery; 1(2). 117–27. ©2011 AACR.

Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL

“…13,15,39 These observations further strengthen the proposed link between LIC activity and PML-RARA loss. 10,14,39 VPA may synergize with ATRA for LIC clearance in vivo We then analyzed the effect of the combination of VPA and ATRA in vivo.…”

“…13,15,39 These observations further strengthen the proposed link between LIC activity and PML-RARA loss. 10,14,39 VPA may synergize with ATRA for LIC clearance in vivo We then analyzed the effect of the combination of VPA and ATRA in vivo. Interestingly, when primary leukemias were pre-treated with VPA for 1 day, PML-RARA protein levels were reduced in ATRA plus VPA-treated mice compared with ATRA-treated ones (Figure 5a), though differentiation was essentially unaltered at 2 days of exposure to drugs (Figure 5b).…”

The PRKAA1/AMPKα1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML

“…37 Importantly, the antileukemic and differentiation effect of ATRA in APL has been recently linked to its ability to induce autophagy-dependent degradation of the PML-RARA/RARa oncoprotein. [38][39][40] The discovery that P2RY6 ligands such as UDP or P2RY6 agonists are able to restore normal differentiation in some CMML patients through the PRKAA1 reactivation is exciting. In agreement with these findings, it has been recently reported that 5-aminoimidazole-4-carboxamide ribonucleoside, an PRKAA activator, enhances ATRA-mediated differentiation of promyelocytic NB4 cells and, as a single agent induces the expression of cell surface markers associated with mature monocytes and macrophages in the acute myeloid leukemia cell line www.tandfonline.comU937.…”

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

“…These findings have important therapeutic relevance, as IFNa promotes PML-and SUMO-dependent degradation of toxic proteins in the brain 62,63 or of the HTLV-I leukemia oncoprotein Tax 64 , with unambiguous clinical benefit 62,65,66 . Thus, similar to therapies based on manipulation of ubiquitin-dependent degradation 67,68 , this could pave the way to IFN-triggered, SUMO-based therapies promoting the proteolytic clearance of undesirable proteins 68 .…”