Acquired resistance to combination treatment with temozolomide and ABT-888 is mediated by both base excision repair and homologous recombination DNA repair pathways.
Many established cancer therapies involve DNA-damaging chemotherapy or radiotherapy. Gain of DNA repair capacity of the tumor represents a common mechanism used by cancer cells to survive DNA-damaging therapy. Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that is activated by DNA damage and plays a critical role in base excision repair. Inhibition of PARP represents an attractive approach for the treatment of cancer. Previously, we have described the discovery and characterization of a potent PARP inhibitor, ABT-888. ABT-888 potentiates the activity of DNA-damaging agents such as temozolomide (TMZ) in a variety of preclinical models. We report here the generation of HCT116 cells resistant to treatment with TMZ and ABT-888 (HCT116R cells). HCT116R cells exhibit decreased H2AX phosphorylation in response to treatment with TMZ and ABT-888 relative to parental HCT116 cells. Microarray and Western blot studies indicate that HCT116R cells have decreased PARP-1 and elevated Rad51 expression levels. HCT116R cells are dependent on Rad51 for proliferation and survival, as shown by inhibition of proliferation and induction of apoptosis upon treatment with Rad51 small interfering RNA. In addition, HCT116R cells are more resistant to radiation than the parental HCT116 cells. Our study suggests that cancer cells upregulate the homologous recombination DNA repair pathway to compensate for the loss of base excision repair, which may account for the observed resistance to treatment with TMZ and ABT-888.
Liu
Xuesong
X
Cancer Research, Abbott Laboratories, Abbott Park, IL 60064, USA. xuesong.liu@abbott.com
Han
Edward K
EK
Anderson
Mark
M
Shi
Yan
Y
Semizarov
Dimitri
D
Wang
Gang
G
McGonigal
Thomas
T
Roberts
Lisa
L
Lasko
Loren
L
Palma
Joann
J
Zhu
Gui-Dong
GD
Penning
Thomas
T
Rosenberg
Saul
S
Giranda
Vincent L
VL
Luo
Yan
Y
Leverson
Joel
J
Johnson
Eric F
EF
Shoemaker
Alexander R
AR
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006657:Histones / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D051135:Rad51 Recombinase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic / Q000187:drug effects* / Q000235:genetics; D017385:Sequence Homology; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; C468783:H2AX protein, human; D006657:Histones; D034741:RNA, Small Interfering; C521013:veliparib; D003606:Dacarbazine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D000077204:Temozolomide