Cancer therapies based on targeted protein degradation - lessons learned with lenalidomide

Abstract

For decades, anticancer targeted therapies have been designed to inhibit kinases or other enzyme classes and have profoundly benefited many patients. However, novel approaches are required to target transcription factors, scaffolding proteins and other proteins central to cancer biology that typically lack catalytic activity and have remained mostly recalcitrant to drug development. The selective degradation of target proteins is an attractive approach to expand the druggable proteome, and the selective oestrogen receptor degrader fulvestrant served as an early example of this concept. Following a long and tragic history in the clinic, the immunomodulatory imide drug (IMiD) thalidomide was discovered to exert its therapeutic activity via a novel and unexpected mechanism of action: targeting proteins to an E3 ubiquitin ligase for subsequent proteasomal degradation. This discovery has paralleled and directly catalysed myriad breakthroughs in drug development, leading to the rapid maturation of generalizable chemical platforms for the targeted degradation of previously undruggable proteins. Decades of clinical experience have established front-line roles for thalidomide analogues, including lenalidomide and pomalidomide, in the treatment of haematological malignancies. With a new generation of 'degrader' drugs currently in development, this experience provides crucial insights into class-wide features of degraders, including a unique pharmacology, mechanisms of resistance and emerging therapeutic opportunities. Herein, we review these past experiences and discuss their application in the clinical development of novel degrader therapies.

Fig. 1 |. Mechanisms of targeted protein degradation.

a | Cullin-RING ligases (CRLs) constitute the largest family of E3 ubiquitin ligases. CRL complexes mediate the selective transfer of ubiquitin (Ub) directly from an E2 enzyme to a receptor-bound substrate protein. This marking with Ub targets the substrate protein for proteasomal degradation. b | Lenalidomide acts as a ‘molecular glue’ to mediate drug-dependent recruitment of neosubstrate proteins to the cereblon (CRBN) receptor component of the cullin-RING ligase CRL4^CRBN, which results in neosubstrate ubiquitination and degradation. c | Thalidomide analogues all share a glutarimide ring that binds to CRBN; however, these agent all vary subtly, in the case of lenalidomide, pomalidomide, and avadomide, or more substantially, in the case of iberdomide and CC-90009, in their neosubstrate-binding moiety. Owing to these chemical variations, different thalidomide analogues promote the degradation of overlapping but distinct sets of neosubstrate proteins.

Fig. 2 |. Event-driven versus occupancy-driven pharmacology.

a | According to the occupancy-driven pharmacological paradigm, small-molecule inhibitors must maintain target-protein occupancy for a sustained antagonistic effect. Moreover, noncatalytic, scaffolding functions of the target protein can be retained and thus continue to contribute to oncogenesis. Furthermore, specific catalytic inhibition of a target protein at the active site, without cross-reactivity within the same protein family, is often challenging. In the figure, the blue shapes represent target proteins, with the active site at the right side and degrader-binding site at the bottom. The blue square represents a separate protein that is able to bind to the target protein regardless of inhibitor occupancy at the active site. The green shape illustrates a protein of the same family as the target that is subject off-target effects of the inhibitor, owing to active site homology, but lacks the degrader-binding site and would, therefore, be spared from off-target degrader effects. b | Degrader drugs deplete the target protein, and functional target inhibition persists until the protein is re-synthesized, constituting an example of event-driven pharmacology. Degraders have a selectivity advantage by mediating ligase–drug–target ternary complex formation using surface interfaces that are generally broader and less conserved than active sites.

Fig. 3 |. Mechanisms of resistance to targeted protein degradation.

a | Tumour cells can escape from thalidomide analogue-induced degradation of key E3 ubiquitin ligase neosubstrate proteins via mutations affecting the cereblon (CRBN)–neosubstrate interface, reduced expression of CRBN or overexpression of competing substrates for the same ligase. b | Tumour cells can escape from the tumour-suppressive consequences of neosubstrate protein degradation through alterations affecting the function of downstream mediators of the antitumour effects. For example, TP53-mutant subclones of del(5q) myelodysplastic syndrome (MDS) haematopoietic stem and progenitor cells (HSPCs) are resistant to p53-mediated apoptosis induce by lenalidomide-mediated degradation of CK1α.

Fig. 4 |. Genetically engineered cell therapies regulated by targeted protein degraders.

The figure outlines an example of the use of lenalidomide as a molecular ‘switch’ to dynamically control the activity of chimeric antigen receptor (CAR) cells. Specifically, a lenalidomide-responsive ‘degron’ moiety (for example, a zinc finger domain derived from IKZF3 can be incorporated in the CAR construct. These degradable constructs can then be used to generate CAR T cells that can be rapidly and reversibly turned ‘off’ through lenalidomide treatment in order to tune CAR signalling or mitigate toxicities associated with T cell hyperactivation. HaloTags or dTags, which also confer the ability to control expression of the engineered protein using small-molecule degraders, could be substituted for the lenalidomide-responsive degron.