Figure 6 | Cell Death Discovery

Figure 6

From: Specific mutations in the D1–D2 linker region of VCP/p97 enhance ATPase activity and confer resistance to VCP inhibitors

Figure 6

Graphical abstract elucidating the in vitro mechanism of resistance to CB-5083. Incremental and prolonged exposure to CB-5083 produced cells that acquired resistance to CB-5058. These cells harbor activating missense mutations at codon 470 (E470K or E470D) of VCP gene in one allele and inactivating nonsense (Q603*) or frameshift stop (N616Mfs*63) mutations in another allele. Although heterozygous mutations in DNA are detected at these sites, only homozygous mutations at codon 470 are detected in cDNA, suggesting that inactivating mutations are subjected to nonsense-mediated decay (NMD). The E470 mutants (E470K/E470D) display enhanced ATPase activity and require higher concentrations of VCP inhibitors to achieve the inhibitory effect.

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