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J Med Oncl Ther 2017 Volume 2 | Issue 3
International Conference on
Oncology and Cancer Therapeutics
October 30- November 01, 2017 | Chicago, USA
The NAE inhibitor MLN4924 inhibits the nucleotide excision repair pathway to enhance the efficacy of
cisplatin treatment in both BRCA1-proficient and –deficient triple negative breast cancers
Alo Ray
Ohio State University Medical Center, USA
D
evelopment of new drugs for TNBC (Triple negative
breast cancer) is urgently needed due to lack of therapy.
NEDD8-activation enzyme (NAE) inhibitor, MLN4924, is
currently in clinical trials. We show that the TNBC cells
show higher sensitivity compared to other breast cancer
subtypes to MLN4924. Furthermore, MLN4924 enhances
the cytotoxicity of the approved TNBC chemotherapeutics
cisplatin but not doxorubicin. Importantly, both BRCA1-
proficient and –deficient cells show re-replication with
>4N DNA content accumulating cells in S phase leading to
apoptosis and senescence. However, the BRCA1-deficient
cells show less re-replication and a higher fraction of cells
progressed to G1 undergoing more senescence. The re-
replication is attributable due to the CDT1 accumulation
via blocking its degradation which triggers DNA damage.
Mechanistic investigation of increased sensitization upon
MLN4924/cisplatin co-treatment revealed that neddylation
substrates, nucleotide excision repair (NER) proteins, DDB2
and XPC play a key role. Neddylation of CUL4 helps DDB2
and XPC ubiquitination, which is essential for cisplatin-DNA
adducts repair by NER. As expected, DDB2 accumulated and
the XPC ubiquitination reduced upon MLN4924 treatment.
Surprisingly, the reduced ubiquitination of XPC promotes
decrease in XPC level. The alterations in the DDB2 and
XPC ubiquitination and their protein levels inhibit NER by
affecting the stoichiometry of repair protein assembly at
the damage sites, and consequently the MLN4924/cisplatin
co-treatment accumulated more cisplatin-DNA adducts.
MLN4924 treatment showed activation of both ATR-Chk1
and ATM-Chk2 cell cycle checkpoint pathways, but the cells
cannot repair the extensive DNA damage. Since MLN4924/
cisplatin treatment shows sensitization of both BRCA1-
proficient and –deficient TNBCs to cisplatin compared to
PARP inhibitor, which sensitizes only BRCA1-deficient TNBC,
this combination will have greater efficacy for all TNBC
patients. We demonstrate a novel mechanism of MLN4924
and cisplatin sensitization and provide a strong rationale for
the clinical investigation of this combination in highly drug
resistant TNBC.
Speaker Biography
Alo Ray has extensive experience in the area of DNA damage repair, cell cycle
checkpoint, and DNA replication all of which play a crucial role in cancer development
and progression. Her research is aimed to investigate the molecular mechanisms
and biological functions of basic cellular processes required for maintaining genomic
stability and integrity with a future goal of developing therapeutic interventions of
cancer. She is using multidisciplinary approaches to target the DNA damage response
repair and cell cycle checkpoint pathways with a goal to enhance the chemo-and
radio-therapy of cancer patients. She has authored several peer-reviewed high-
profile journals such as
Nature Genetics, PNAS, Molecular Cell, NAR, MCB
, and
DNA
repair
. She was granted the Leukemia & Lymphoma Society Special Fellowship Award.
Additionally, she was granted several grants as Principal Investigator and Co-Principal
Investigator from American Cancer Society, OSU Cancer Center and NIH.
e:
alo.ray@osumc.edu