Reference Detail

Ref Type

Journal Article

PMID

(36329119)

Authors

Hanzl A, Casement R, Imrichova H, Hughes SJ, Barone E, Testa A, Bauer S, Wright J, Brand M, Ciulli A, Winter GE

Title

Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature chemical biology			2022 Nov 03	323-333	Nat Chem Biol

URL

Abstract Text

Targeted protein degradation is a novel pharmacology established by drugs that recruit target proteins to E3 ubiquitin ligases. Based on the structure of the degrader and the target, different E3 interfaces are critically involved, thus forming defined 'functional hotspots'. Understanding disruptive mutations in functional hotspots informs on the architecture of the assembly, and highlights residues susceptible to acquire resistance phenotypes. Here we employ haploid genetics to show that hotspot mutations cluster in substrate receptors of hijacked ligases, where mutation type and frequency correlate with gene essentiality. Intersection with deep mutational scanning revealed hotspots that are conserved or specific for chemically distinct degraders and targets. Biophysical and structural validation suggests that hotspot mutations frequently converge on altered ternary complex assembly. Moreover, we validated hotspots mutated in patients that relapse from degrader treatment. In sum, we present a fast and widely accessible methodology to characterize small-molecule degraders and associated resistance mechanisms.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
VHL	H110L	missense	unknown	VHL H110L lies within the CCT complex-binding region of the Vhl protein (UniProt.org). H110L has been identified in the scientific literature (PMID: 36329119), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Apr 2024).
VHL	W117*	nonsense	loss of function - predicted	VHL W117* results in a premature truncation of the Vhl protein at amino acid 117 of 213 (UniProt.org). W117* has not been characterized, however, is associated with resistance to BET inhibitors in culture (PMID: 36329119) and due to the effects of other truncation mutations downstream of W117 (PMID: 14691445), is predicted to lead to a loss of Vhl protein function.	Y
VHL	Y112C	missense	unknown	VHL Y112C lies within the CCT complex-binding region of the Vhl protein (UniProt.org). Y112C has been demonstrated to confer resistance to BET inhibitors in culture (PMID: 36329119), but has not been biochemically characterized and therefore, its effect on Vhl protein function is unknown (PubMed, Jun 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
VHL S139fs	leukemia	resistant	ARV-771	Preclinical - Cell culture	Actionable	In a preclinical study, a leukemia cell line demonstrated resistance to ARV-771 and was found to have acquired VHL S139fs in culture (PMID: 36329119).	36329119
VHL Y112C	colon carcinoma	resistant	ARV-771	Preclinical - Cell culture	Actionable	In a preclinical study, a colon carcinoma cell line expressing VHL Y112C was resistant to ARV-771 in culture (PMID: 36329119).	36329119
VHL H110L	colon carcinoma	sensitive	ARV-771	Preclinical - Cell culture	Actionable	In a preclinical study, ARV-771 inhibited viability in a colon carcinoma cell line expressing VHL H110L in culture (PMID: 36329119).	36329119
VHL S111R	leukemia	resistant	ARV-771	Preclinical - Cell culture	Actionable	In a preclinical study, a leukemia cell line demonstrated resistance to ARV-771 and was found to have acquired VHL S111R in culture (PMID: 36329119).	36329119
VHL W117*	leukemia	resistant	ARV-771	Preclinical - Cell culture	Actionable	In a preclinical study, a leukemia cell line demonstrated resistance to ARV-771 and was found to have acquired VHL W117* in culture (PMID: 36329119).	36329119
VHL Y112C	leukemia	resistant	ARV-771	Preclinical - Cell culture	Actionable	In a preclinical study, a leukemia cell line demonstrated resistance to ARV-771 and was found to have acquired VHL Y112C in culture (PMID: 36329119).	36329119
VHL V166F	leukemia	resistant	ARV-771	Preclinical - Cell culture	Actionable	In a preclinical study, a leukemia cell line demonstrated resistance to ARV-771 and was found to have acquired VHL V166F in culture (PMID: 36329119).	36329119