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

Most emerging mutations occur directly in the SR of the involved E3 ligase.

“In line with previous studies that employed CRISPR/Cas9 screens13–15, we show that most emerging mutations occur directly in the SR of the involved E3 ligase.”

Several functional genomics campaigns have helped map how the repertoire of CRLs and their regulators shape degrader efficacy, outlining putative resistance mechanisms.

“Several functional genomics campaigns in recent years have helped map how the repertoire of CLRs and their regulators shape degrader efficacy, thus also outlining putative resistance mechanisms.141-151”

PROTACs were shown to be substrates for MDR1.

“Recently, PROTACs were shown to be substrates for MDR1 (10, 13), suggesting that drug efflux represents a potential limitation for degrader therapies.”

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).”

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.”

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.”

E3 ligases and other UPS genes such as CDC20, CIAO1 and WDR82 exhibit high tumour essentiality across many different cancer cell types.

“This has allowed the identification of E3 ligases and other UPS genes — some better-characterized than others, such as cell division cycle 20 (CDC20), cytosolic iron–sulfur assembly component 1 (CIAO1) and WD repeat-containing protein 82 (WDR82) — that exhibit high tumour essentiality across many different cancer cell types99.”

Several recent reviews have analysed publicly available datasets for ligase expression in healthy and diseased states to highlight ligases with clear and distinct expression profiles.

“several recent reviews have analysed and categorized publicly available datasets — such as GTEx, The Cancer Genome Atlas (TCGA), ProteinAtlas and others — for ligase expression in healthy and diseased states, to highlight ligases with clear and distinct expression profiles80,99,143,144.”