Journal
FUTURE ONCOLOGY
Volume 17, Issue 23, Pages 3051-3060Publisher
FUTURE MEDICINE LTD
DOI: 10.2217/fon-2021-0256
Keywords
5-FU; cobimetinib; combination index; MAPK; MEK inhibitor; Raf; MEK; ERK; renal cell carcinoma; sorafenib; sunitinib; synergy
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Funding
- Sichuan Provincial Department of Science and Technology Applied Basic Research Program [2019YJ0711]
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Cobimetinib demonstrates potent anti-RCC activity and synergizes with standard-of-care drugs by suppressing the Raf/MEK/ERK pathway and enhancing the efficacy of other treatments.
Background: The poor outcome of advanced renal cell carcinoma (RCC) necessitates new treatments. Cobimetinib is a MEK inhibitor and approved for the treatment of melanoma. This work investigated the efficacy of cobimetinib alone and in combination with anti-RCC drugs. Methods: Proliferation and apoptosis assays were performed, and combination index was analyzed on RCC cell lines (CaKi-2, 786-O, A-704, ACHN and A489) and xenograft models. Immunoblotting analysis was conducted to investigate the MAPK pathway. Results: Cobimetinib was active against RCC cells, with IC50 at 0.006-0.8 mu M, and acted synergistically with standard-of-care therapy. Cobimetinib at nontoxic doses prevented tumor formation, inhibited tumor growth and enhanced efficacy of 5-fluorouracil, sorafenib and sunitinib via suppressing Raf/MEK/ERK, leading to MAPK pathway inhibition. Conclusion: Our findings demonstrate the potent anti-RCC activity of cobimetinib and its synergism with RCC standard-of-care drugs, and confirm the underlying mechanism of the action of cobimetinib.
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