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. Author manuscript; available in PMC: 2022 Mar 8.
Published in final edited form as: Nat Rev Clin Oncol. 2021 Mar 2;18(7):401–417. doi: 10.1038/s41571-021-00479-z

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

Fig. 3 |

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.