2.2.5 CC-122
CC-122 is a next-generation brain E3 ligase regulator, and Zhongying Mo
et al 45 performed a genome-wide CRISPR / Cas9 screen
for CC-122 in the DLBCL cell line SU-DHL-4, enriched for the
CUL4/DDB1/RBX1/CRBN E3 ubiquitin ligase complex or regulator, which
induced IKZF1 and IKZF3 proteins ubiquitination and degradation,
resulting in enhanced antiproliferative effects of CC-122 in DLBCL cells46. The sgRNAs targeting the NF-κB inhibitory genes
CYLD, NFKBIA, TRAF2 and TRAF3 also showed significant enrichment in
SU-DHL-4 cells, indicating that inhibition of the NF-κB pathway enhanced
the anti-tumor activity of CC-122 in DLBCL. The elimination of CRBN
showed more resistance to CC-122 than CYLD, NFKBIA, TRAF2 or TRAF3
inactivation, and the knockdown effect of CYLD and NFKB1A was also more
pronounced than TRAF2 and TRAF3. Furthermore, knockdown of KCTD5, RFX7
and AMBRA1 in CRISPR screens abrogated the response to CC-122, and
accumulation of the Gβγ subunit GNG5 after KCTD5 depletion reduced the
growth inhibitory effect of CC-122 in several DLBCL cell lines. RFX7 and
AMBRA1 are key factors in CC-122 apoptosis, RFX7 and Ambra1 loss will
lead to V-7-AAD cell loss.