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Functional Genomics Identify Distinct and Overlapping Genes Mediating Resistance to Different Classes of Heterobifunctional Degraders of Oncoproteins.

Abstract：

:Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases to induce degradation of target oncoproteins and exhibit potent preclinical antitumor activity. To dissect the mechanisms regulating tumor cell sensitivity to different classes of pharmacological "degraders" of oncoproteins, we performed genome-scale CRISPR-Cas9-based gene editing studies. We observed that myeloma cell resistance to degraders of different targets (BET bromodomain proteins, CDK9) and operating through CRBN (degronimids) or VHL is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein; and this involves loss of function of the cognate E3 ligase or interactors/regulators of the respective cullin-RING ligase (CRL) complex. The substantial gene-level differences for resistance mechanisms to CRBN- versus VHL-based degraders explains mechanistically the lack of cross-resistance with sequential administration of these two degrader classes. Development of degraders leveraging more diverse E3 ligases/CRLs may facilitate sequential/alternating versus combined uses of these agents toward potentially delaying or preventing resistance.

journal_name

Cell Rep

journal_title

Cell reports

authors

Shirasaki R,Matthews GM,Gandolfi S,de Matos Simoes R,Buckley DL,Raja Vora J,Sievers QL,Brüggenthies JB,Dashevsky O,Poarch H,Tang H,Bariteau MA,Sheffer M,Hu Y,Downey-Kopyscinski SL,Hengeveld PJ,Glassner BJ,Dhimolea E,O

doi

10.1016/j.celrep.2020.108532

subject

Has Abstract

pub_date

2021-01-05 00:00:00

pages

108532

issue

1

issn

2211-1247

pii

S2211-1247(20)31521-7

journal_volume

34

pub_type

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