Acquired Resistance to BET-PROTACs (Proteolysis-Targeting Chimeras) Caused by Genomic Alterations in Core Components of E3 Ligase Complexes
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Abstract
Proteolysis-targeting chimeras (PROTAC) are bifunctional molecules that hijack endogenous E3 ubiquitin ligases to induce ubiquitination and subsequent degradation of protein of interest. Recently, it has been shown that PROTACs with robust in vitro and in vivo activities and, in some cases, drug-like pharmaceutical properties can be generated using small-molecule ligands for the E3 ligases VHL and CRBN. These findings stoked tremendous enthusiasm on using PROTACs for therapeutics development. Innate and acquired drug resistance often underlies therapeutic failures, particularly for cancer therapy. With the PROTAC technology progressing rapidly toward therapeutic applications, it would be important to understand whether and how resistance to these novel agents may emerge. Using BET-PROTACs as a model system, we demonstrate that resistance to both VHL- and CRBN-based PROTACs can occur in cancer cells following chronic treatment. However, unlike what was often observed for many targeted therapeutics, resistance to BET-PROTACs did not result from secondary mutations that affect compound binding to the target. In contrast, acquired resistance to both VHL- and CRBN-based BET-PROTACs was primarily caused by genomic alterations that compromise core components of the relevant E3 ligase complexes.
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Loss of CUL2 has previously been reported as an acquired resistance mechanism to VHL-based PROTACs in OVCAR8 cells.
“Supporting these results, loss of CUL2 has previously been reported as an acquired resistance mechanism to VHL-based PROTACs in OVCAR8 cells16.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [16]
Resistance to PROTACs in cultured cells has been shown to involve genomic alterations in their E3 ligase targets, such as decreased expression of CRBN, VHL, or CUL2.
“Resistance to PROTACs in cultured cells has been shown to involve genomic alterations in their E3 ligase targets, such as decreased expression of Cereblon (CRBN), Von Hippel Lindau (VHL), or Cullin2 (CUL2) (9–11).”
From The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells (2022) · cites this paper as [11]
Preclinical studies of degraders that use CRBN or VHL to target multiple protein classes have detected emerging resistance via mutation and/or downregulation of components of the ubiquitin ligase machinery.
“In fact, preclinical studies of degraders that use CRBN or VHL to target multiple protein classes have detected emerging resistance that occurs via mutation and/or downregulation of components of the ubiquitin ligase machinery99–101.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [100]
Ligase-based resistance has been shown to occur for some CRBN- and VHL-recruiting PROTACs.
“which has been shown to occur for some CRBN- and VHL-recruiting PROTACs, as discussed previously.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [100]
Resistance to both VHL- and CRBN-based PROTACs was reported in cancer cells following chronic treatment, primarily led by genomic alterations that compromise core components of the relevant E3 ligase complexes.
“resistance to both VHL- and CRBN-based PROTACs was reported in cancer cells following chronic treatment, which was primarily led by genomic alterations that compromise core components of the relevant E3 ligase complexes [241].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [241]
Acquired resistance to PROTAC treatment can be driven by genomic alterations targeting core components of E3 ligase complexes.
“Acquired resistance to PROTAC treatment can be driven by genomic alterations targeting core components of E3 ligase complexes 35 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [35]
Genomic alteration of E3 ligase complexes is a resistance mechanism used by cancer cells in response to chronic treatment with VHL- or CRBN-recruiting PROTACs.
“Genomic alteration of E3 ligase complexes is a resistance mechanism used by cancer cells in response to chronic treatment with VHL or CRBN-recruiting PROTACs 35 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [35]
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References 35 · Cited by 365
- Authors
- Zhang, L., Riley-Gillis, B., Vijay, P., & Shen, Y.
- Affiliations
- AbbVie (United States) (US)
- Venue
- Molecular Cancer Therapeutics
- Published
- 2019-07-01
- Volume
- 18
- Issue
- 7
- Pages
- 1302-1311
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W2944640816
- Cited by
- 365
- References
- 35
- Citations by year
- 2026: 69 · 2025: 45 · 2024: 69 · 2023: 50 · 2022: 50 · 2021: 29 · 2020: 46 · 2019: 6
- FWCI
- 10.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AbbVieAbbVie (Abbvie)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- PROTACs, acquired drug resistance, E3 ubiquitin ligase, VHL, cereblon, genetic alterations, ubiquitination, protein degradation, long-term treatment, cancer therapy
- MeSH terms
- Humans, Genomics, Ubiquitin-Protein Ligases, Cell Line, Tumor, Proteolysis
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