TY - JOUR
T1 - VLX600 disrupts homologous recombination and synergizes with PARP inhibitors and cisplatin by inhibiting histone lysine demethylases
AU - Ekstrom, Thomas L.
AU - Pathoulas, Nicholas M.
AU - Huehls, Amelia M.
AU - Kanakkanthara, Arun
AU - Karnitz, Larry M.
N1 - Publisher Copyright:
© 2021 The Authors; Published by the American Association for Cancer Research
PY - 2021/9
Y1 - 2021/9
N2 - Tumors with defective homologous recombination (HR) DNA repair are more sensitive to chemotherapies that induce lesions repaired by HR as well as PARP inhibitors (PARPis). However, these therapies have limited activity in HR-proficient cells. Accordingly, agents that disrupt HR may be a means to augment the activities of these therapies in HR-proficient tumors. Here we show that VLX600, a small molecule that has been in a phase I clinical trial, disrupts HR and synergizes with PARPis and platinum compounds in ovarian cancer cells. We further found that VLX600 and other iron chelators disrupt HR, in part, by inhibiting iron-dependent histone lysine demethylases (KDM) family members, thus blocking recruitment of HR repair proteins, including RAD51, to double-strand DNA breaks. Collectively, these findings suggest that pharmacologically targeting KDM family members with VLX600 may be a potential novel strategy to therapeutically induce HR defects in ovarian cancers and correspondingly sensitize them to platinum agents and PARPis, two standard-of-care therapies for ovarian cancer.
AB - Tumors with defective homologous recombination (HR) DNA repair are more sensitive to chemotherapies that induce lesions repaired by HR as well as PARP inhibitors (PARPis). However, these therapies have limited activity in HR-proficient cells. Accordingly, agents that disrupt HR may be a means to augment the activities of these therapies in HR-proficient tumors. Here we show that VLX600, a small molecule that has been in a phase I clinical trial, disrupts HR and synergizes with PARPis and platinum compounds in ovarian cancer cells. We further found that VLX600 and other iron chelators disrupt HR, in part, by inhibiting iron-dependent histone lysine demethylases (KDM) family members, thus blocking recruitment of HR repair proteins, including RAD51, to double-strand DNA breaks. Collectively, these findings suggest that pharmacologically targeting KDM family members with VLX600 may be a potential novel strategy to therapeutically induce HR defects in ovarian cancers and correspondingly sensitize them to platinum agents and PARPis, two standard-of-care therapies for ovarian cancer.
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U2 - 10.1158/1535-7163.MCT-20-1099
DO - 10.1158/1535-7163.MCT-20-1099
M3 - Article
C2 - 34224364
AN - SCOPUS:85114252007
SN - 1535-7163
VL - 20
SP - 1561
EP - 1571
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 9
ER -