Birinapant (TL32711) Improves Responses to GEM/AZD7762 Combination Therapy in Triple-negative Breast Cancer Cell Lines.
BACKGROUND
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer currently lacking targeted therapies. Our previous work demonstrated a therapeutic synergism with gemcitabine (GEM) and the CHK1 inhibitor (AZD7762) combination treatment in a TNBC cell line. We hypothesized that the response to this combination therapy would differ among heterogeneous TNBC patients and that addition of a SMAC mimetic (TL32711) could improve efficacy.


METHODS
Therapeutic responses to GEM, GEM/AZD7762, and GEM/AZD7762/TL32711 combinations were investigated by XTT assays and western blotting of cell cycle and apoptosis-related proteins in ten TNBC cell lines.


RESULTS
TNBC cell lines harboring low levels of endogenous CHK1, cIAP1 and cIAP2 were responsive to GEM alone, whereas cell lines demonstrating a minimal increase in phospho-S345 CHK1 after treatment were responsive to GEM/AZD7762 or GEM/AZD7762/TL32711 combination.


CONCLUSIONS
The response of TNBC cells to particular therapies varies and will require development of predictive biomarkers.
Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, U.S.A.
Dong-Joon
DJ
Min
Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, U.S.A.
Siping
S
He
Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD, U.S.A. jegreen@nih.gov.
Jeffrey E
JE
Green
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1 / Q000378:metabolism; D004260:DNA Repair; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004151:Dipeptides / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D010766:Phosphorylation; D013876:Thiophenes / Q000008:administration & dosage*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000093542:Gemcitabine
C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; D004151:Dipeptides; D007211:Indoles; D013876:Thiophenes; D003841:Deoxycytidine; C582429:birinapant; D014508:Urea; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D000093542:Gemcitabine
CHK1; Combination treatment; TL32711; triple-negative breast cancer