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
1908 - Androgen Receptor (AR) Aberrations in Patients (Pts) With Metastatic Castration-Sensitive Prostate Cancer (mCSPC) Treated With Apalutamide (APA) Plus Androgen Deprivation Therapy (ADT) in TITAN
Presenter: Kim Chi
Session: Poster Display session 3
Resources:
Abstract
4058 - 68Ga-PSMA guided bone biopsies for molecular diagnostics in metastatic castration resistant prostate cancer patients
Presenter: Anouk de Jong
Session: Poster Display session 3
Resources:
Abstract
2226 - Spatial-Temporal Change in Quantitative Total Bone Imaging (QTBI) and Circulating Tumor Cells (CTCs) in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated With Enzalutamide (ENZA)
Presenter: Glenn Liu
Session: Poster Display session 3
Resources:
Abstract
5795 - Efficacy of Enzalutamide in Hormone-sensitive Metastatic Prostate Cancer: Clinical Utility of 18F-Choline PET and Whole Body MRI.
Presenter: Susanne Osanto
Session: Poster Display session 3
Resources:
Abstract
899 - Urine extracellular vesicle GATA2 mRNA alone and in a multigene test predicts initial prostate biopsy result
Presenter: Jungreem Woo
Session: Poster Display session 3
Resources:
Abstract
3094 - Circulating tumor cell (CTC) genomic landscape in neuroendocrine prostate cancer (NEPC) by single cell copy number analysis
Presenter: Vincenza Conteduca
Session: Poster Display session 3
Resources:
Abstract
2527 - Circulating Tumor Cells (CTC) count and Prostate-Specific Antigen (PSA) response measures in metastatic Castration-Resistant Prostate Cancer (mCRPC) patients (pts) treated with Docetaxel (Doc)
Presenter: Rebeca Lozano Mejorada
Session: Poster Display session 3
Resources:
Abstract
6106 - Assessing the clinical relevance of drug–drug interactions (DDI) with darolutamide (DARO)
Presenter: Christian Zurth
Session: Poster Display session 3
Resources:
Abstract
2237 - KEYNOTE-921: phase 3 study of pembrolizumab (pembro) plus docetaxel and prednisone for enzalutamide (enza)- or abiraterone (abi)-pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Presenter: Daniel Petrylak
Session: Poster Display session 3
Resources:
Abstract
2241 - KEYNOTE-641: Phase 3 Study of Pembrolizumab (pembro) Plus Enzalutamide for Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Presenter: Julie Graff
Session: Poster Display session 3
Resources:
Abstract