Abstract 1829
Background
Eribulin is one of the well-tolerated microtubule dynamics inhibitor made in Japan, and it has been reported to be especially effective for triple negative breast cancer (TNBC) with poor prognosis. We previously reported the possibility of the combination treatment of eribulin and a novel HDAC inhibitor OBP-801 for the promising strategy against TNBC patients. We also interestingly showed that the combination more potently suppressed a MAPK pathway than each agent. Therefore, in this study we investigated the effect of new combination therapy, eribulin and a RAF/MEK inhibitor in TNBC.
Methods
We used CH5126766 as a novel RAF/MEK inhibitor. The phase I clinical trial of CH5126766 is now in progress in the U.S. We investigated the combination effect of eribulin and CH5126766 using some TNBC cell lines. The cell growth was analyzed through WST-8 assay and colony formation assay, and the flow cytometry analysis was conducted to evaluate the induction of apoptosis. The mechanism underlying the enhancement of inhibition of TNBC growth was investigated through Western blot analyses. We also analyzed the combination effect through the onco-immunological mechanism.
Results
The combination treatment showed the inhibition of the TNBC cell growth in both short and long incubation. The mechanism of this combination is due to the enhancement of apoptosis. The apoptosis in the combination was induced with the suppression of anti-apoptotic protein survivin in the TNBC cells. Though eribulin upregulated survivin, CH5126766 could potently suppress the survivin expression induced by eribulin. On the other hand, eribulin could suppress the Akt pathway induced as the result of the resistance of the MAPK pathway. Moreover, CH5126766 might be effective in this combination through the onco-immunological mechanism.
Conclusions
We found that the combination of eribulin and CH5126766 inhibits the growth with apoptosis in TNBC, raising the possibility that the combination might be a novel promising strategy for patients suffering from TNBC with the upregulation of MAPK pathway.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
T. Sakai: Research grant / Funding (institution), Licensing / Royalties: Chugai. All other authors have declared no conflicts of interest.
Resources from the same session
5705 - External validation and longitudinal extension of the LIPI (Lung Immune Prognostic Index) for immunotherapy outcomes in advanced non-small cell lung cancer.
Presenter: Jakob Riedl
Session: Poster Display session 3
Resources:
Abstract
5758 - Changes of TCR Repertoire in Metastatic Renal Cell Carcinoma and Metastatic Melanoma Patients Treated with Nivolumab
Presenter: Martin Klabusay
Session: Poster Display session 3
Resources:
Abstract
1743 - Expression of MHC class I, HLA-A and HLA-B identifies immune activated breast tumors with favorable outcome
Presenter: María Del Mar Noblejas López
Session: Poster Display session 3
Resources:
Abstract
2219 - Prognostic Significance of Tumor Tissue NeuGcGM3 Ganglioside Expression and Predictive Value of Circulating Tumor Cell Count Monitoring in Patients Receiving Racotumomab Immunotherapy
Presenter: Necdet Üskent
Session: Poster Display session 3
Resources:
Abstract
2996 - Evolution of Myeloid-Derived Suppressor Cells and Objective Response Rate in Relapsed/Refractory Diffuse Large B Cell Lymphoma (R/R DLBCL) patients after receiving immunotherapy
Presenter: Carlos Jiménez Cortegana
Session: Poster Display session 3
Resources:
Abstract
2110 - A Phase Ia/Ib trial of the anti-programmed death-ligand 1 (PD-L1) human monoclonal antibody (mAb), CS1001, in patients (pts) with advanced solid tumors or lymphomas
Presenter: Lin Shen
Session: Poster Display session 3
Resources:
Abstract
3515 - Results from a randomised Phase 1/2 trial evaluating the safety and antitumour activity of anti-PD-1 (MEDI0680)/anti-PD-L1 (durvalumab) vs anti-PD-1 (nivolumab) alone in metastatic clear cell renal cell carcinoma (ccRCC)
Presenter: Martin Voss
Session: Poster Display session 3
Resources:
Abstract
3566 - Pembrolizumab in Advanced Rare Cancers
Presenter: Aung Naing
Session: Poster Display session 3
Resources:
Abstract
3567 - High clinical benefit rates of pembrolizumab in very rare sarcoma histotypes: first results of the AcSé Pembrolizumab study
Presenter: Jean-Yves Blay
Session: Poster Display session 3
Resources:
Abstract
2421 - Lenvatinib plus PD-1 blockade in advanced bile tract carcinoma.
Presenter: Jianzhen Lin
Session: Poster Display session 3
Resources:
Abstract