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Updated: Nov 21, 2025

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
10:44

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

13.5K

Multiple cereblon genetic changes are associated with acquired resistance to lenalidomide or pomalidomide in multiple

Sarah Gooding1,2,3,4, Naser Ansari-Pour3,5, Fadi Towfic6

  • 1MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.

Blood
|January 14, 2021
PubMed

Insights

Drug resistance in myeloma is a major challenge. This study reveals increasing Cereblon (CRBN) alterations with immunomodulatory drug (IMiD) exposure, impacting treatment outcomes and guiding CRBN-targeted therapy selection.

Area of Science:

  • Myeloma therapeutics
  • Genomic alterations in cancer
  • Drug resistance mechanisms

Background:

  • Cereblon (CRBN) is a key target for immunomodulatory drugs (IMiDs) and novel CELMoDs in myeloma treatment.
  • Drug resistance, particularly to IMiDs, significantly limits survival improvements in multiple myeloma.
  • Understanding CRBN alterations is crucial for developing effective sequential therapies.

Purpose of the Study:

  • To comprehensively analyze the frequency and types of CRBN aberrations in myeloma patients undergoing sequential therapies.
  • To investigate the association between CRBN alterations and treatment outcomes with pomalidomide (POM) in lenalidomide (LEN)-refractory patients.
  • To establish the largest dataset to date on CRBN alterations in progressing myeloma.

Main Methods:

  • Whole-genome sequencing (WGS) and RNA sequencing (RNASeq) data from 455 and 655 myeloma patients, respectively.
  • Analysis of newly diagnosed, LEN-refractory, and POM-refractory patient cohorts.
  • Assessment of CRBN point mutations, copy losses/structural variations, and a specific variant transcript (exon 10 spliced).

Main Results:

  • CRBN aberrations (point mutations, copy losses/structural variations, exon 10 splicing) increased with progressive IMiD exposure, reaching nearly one-third in POM-refractory patients.
  • All three CRBN aberration types were associated with inferior outcomes to POM in patients previously refractory to LEN.
  • Gene copy losses and structural variations showed a previously undescribed association with poor POM response.

Conclusions:

  • CRBN alterations accumulate with sequential IMiD therapy in myeloma, representing a significant mechanism of resistance.
  • The presence of CRBN aberrations predicts poor response to pomalidomide in lenalidomide-refractory patients.
  • This comprehensive analysis provides critical insights for patient selection in sequential CRBN-targeted therapies for myeloma.

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