Table 1.

Representative regulators of targeted protein degradation involved in drug resistance

Protein degradation regulator	Category	Substrate	Therapeutic agents	Role	Tumor	Mechanism	Refs.
FBXO15	E3	P-gp	Vincristine and doxorubicin	Sensitive	CRC	Drug efflux	[54]
FBXO21	E3	P-gp	Valinomycin	Sensitive	Ovarian cancer	Drug efflux	[57]
MARCH8	E3	P-gp	Adriamycin, paclitaxel, and colchicine	Sensitive	Breast cancer, NSCLC	Drug efflux	[60]
AMFR	E3	P450s	Enzalutamide	Resistant	–	Drug metabolism	[77]
FBXW7	E3	BRAF	BET inhibitors	Sensitive	T cell leukemia	Altering drug target	[190]
Cbl-b	E3	EGFR	Adriamycin	Resistant	BC/GC	Altering drug target	[160]
SIAH2	E3	CHK2	Genotoxic agents	Sensitive	Multiple cancer types	DNA repair	[118]
MDM2	E3	p53	Cisplatin	Resistant	Uveal melanoma, ovarian cancer, lung cancer	DNA repair	[120–122]
TRIM28	E3	TRDMT1	DNA-damaging agents	Sensitive	Ovarian cancer	DNA repair	[139]
RNF144A	E3	DNA-PKcs	DNA-damaging agents	Sensitive	Multiple cancer types	DNA repair	[140]
CHIP	E3	BCL-2	Chemotherapy	Sensitive	Breast cancer	Apoptosis	[214]
CRL4	E3	STAT1	Cisplatin	Resistant	Ovarian cancer	Apoptosis	[215]
RNF44	E3	AMPK-α1	BRAFi	Resistant	Melanoma	Oncogenic bypass signaling	[225]
CHIP	E3	MAST1	Cisplatin	Sensitive	Multiple cancer types	Oncogenic bypass signaling	[227]
SIAH1	E3	ZEB1	Doxorubicin	Sensitive	HCC	EMT	[240]
FBXO32	E3	Snail	Platinum	Sensitive	Urothelial carcinoma	EMT	[242]
β-TrCP	E3	β-catenin and YAP	Vinorelbine and docetaxel	Sensitive	Triple-negative breast cancer	Stemness	[248]
β-TrCP	E3	NRF2	Temozolomide	Sensitive	Glioma	ROS signaling	[273]
β-TrCP	E3	NRF2	Chemotherapy	Sensitive	Pancreatic cancer	ROS signaling	[274]
USP28	DUB	BRAF	BRAF inhibitors	Resistant	Melanoma	Altering drug target	[191]
USP14	DUB	BRAF	BRAF inhibitors	Resistant	Melanoma	Altering drug target	[193]
USP22	DUB	EGFR	EGFR-TKIs	Resistant	Lung adenocarcinoma		[169]
USP17	DUB	EGFR	EGFR-TKIs	Resistant	NSCLC	Altering drug target	[292]
UCHL1	DUB	EGFR	EGFR-TKIs	Resistant	Breast cancer	Altering drug target	[170]
USP7	DUB	MDC1	Genotoxic insults	Resistant	Cervical cancer	DNA repair	[101]
USP7	DUB	CHK1	Cytarabine	Resistant	Acute myeloid leukemia	DNA repair	[104]
USP7	DUB	CDC25A	DNA-damaging agents	Resistant	Cervical cancer	DNA repair	[106]
USP7	DUB	PLK1	Taxane	Resistant	Lung cancer	DNA repair	[111]
USP24	DUB	p53	Radiation	Sensitive		DNA repair	[112]
USP28	DUB	p53	Genotoxic chemotherapy	Sensitive	Multiple cancer types	DNA repair	[113]
USP39	DUB	CHK2	Chemotherapy drugs and radiation treatment	Sensitive	Lung cancer	DNA repair	[114]
USP3	DUB	Claspin	Radiation	Resistant	Glioblastoma	DNA repair	[115]
USP9x	DUB	BRCA1	DNA-damaging agents	Resistant	Multiple cancer types	DNA repair	[134]
USP10	DUB	MSH2	N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) and 6-thioguanine (6-TG)	Sensitive	Lung cancer	DNA repair	[148]
USP2	DUB	cFLIP	Sorafenib	Resistant	Hepatocellular carcinoma	Apoptosis	[209]
USP17	DUB	Mcl-1	Platinum and paclitaxel	Resistant	Ovarian cancer	Apoptosis	[292]
USP9x	DUB	Mcl-1	Ionizing radiation	Resistant	Oral cancer	Apoptosis	[206]
USP15	DUB	Caspase-6	Imatinib	Sensitive	Chronic myeloid leukemia	Apoptosis	[210]
USP1	DUB	Snail	Platinum	Resistant	Ovarian cancer	EMT	[243]
USP51	DUB	ZEB1	Cisplatin	Resistant	Lung cancer	EMT	[293]
USP20	DUB	β-catenin	Chemotherapy	Resistant	Breast cancer	Stemness	[249]
USP22	DUB	β-catenin	5-fluorouracil	Resistant	Colorectal cancer	Stemness	[252]
USP10	DUB	YAP	Chemotherapy	Resistant	Breast cancer	Stemness	[256]
USP17	DUB	NRF2	Camptothecin and paclitaxel	Resistant	Colorectal cancer	ROS signaling	[292]
USP15	DUB	KEAP1	Chemotherapy	Sensitive	Multiple cancer types	ROS signaling	[271, 272]
USP29	DUB	HIF-1α	Sorafenib	Resistant	Hepatocellular carcinoma	Hypoxia	[287]
Hsc70	Chaperone	HOXB13	Tamoxifen	Sensitive	Breast cancer	Microenvironment	[281]
Hsc70	Chaperone	MORC2	Antiestrogen therapies	Sensitive	Breast cancer	DNA repair	[124]