1940PA novel RAF/MEK inhibitor CH5126766 in phase I clinical trial has an effectiveness in the combination with eribulin for the treatment of triple negative breast cancer

Abstract 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. 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.