alvespimycin

Overview

Alvespimycin (17-DMAG) is a water-soluble geldanamycin analogue that inhibits HSP90. It is the reduced, active metabolite form of tanespimycin (17-AAG). NQO1 reduces 17-AAG to 17-DMAG in tumors, meaning NQO1 expression modulates sensitivity to both agents. GI50 for alvespimycin is inversely correlated with NQO1 expression in liver cancer cell lines.

Evidence in the corpus

• HSP90 inhibitors tanespimycin (17-AAG) and alvespimycin (17-DMAG) nominated as candidate strategies for KEAP1/NFE2L2-mutated HCC: GI50 for 17-AAG/17-DMAG was inversely correlated with NQO1 expression (Pearson r = −0.56, P = 0.0015) across 29 liver cancer cell lines; two of three KEAP1-mutant lines were highly sensitive; the third (MHCC97H) was resistant due to homozygous NQO1 P187S (rs1800566) variant that destabilizes NQO1 protein PMID:25822088

Resistance mechanisms

• NQO1 P187S (rs1800566) polymorphism destabilizes NQO1 protein and confers resistance to alvespimycin/tanespimycin in KEAP1-mutated HCC cell line MHCC97H PMID:25822088

Cancer types (linked)

• HCC

Sources

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