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Ryabaya OO, Abramov IS, Khochenkov DA, et al. Rapamycin synergizes the cytotoxic effects of MEK inhibitor binimetinib and overcomes acquired resistance to therapy in melanoma cell lines in vitro. Invest New Drugs. 2021;39(4):987-1000doi: 10.1007/s10637-021-01089-3.
Ryabaya, O. O., Abramov, I. S., Khochenkov, D. A., Akasov, R., Sholina, N. V., & Prokofieva, A. A. (2021). Rapamycin synergizes the cytotoxic effects of MEK inhibitor binimetinib and overcomes acquired resistance to therapy in melanoma cell lines in vitro. Investigational new drugs, 39(4), 987-1000. https://doi.org/10.1007/s10637-021-01089-3
Ryabaya, Oxana O, et al. "Rapamycin synergizes the cytotoxic effects of MEK inhibitor binimetinib and overcomes acquired resistance to therapy in melanoma cell lines in vitro." Investigational new drugs vol. 39,4 (2021): 987-1000. doi: https://doi.org/10.1007/s10637-021-01089-3
Ryabaya OO, Abramov IS, Khochenkov DA, Akasov R, Sholina NV, Prokofieva AA. Rapamycin synergizes the cytotoxic effects of MEK inhibitor binimetinib and overcomes acquired resistance to therapy in melanoma cell lines in vitro. Invest New Drugs. 2021 Aug;39(4):987-1000. doi: 10.1007/s10637-021-01089-3. Epub 2021 Mar 08. PMID: 33683500.
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Invest New Drugs. 2021 Aug;39(4):987-1000. doi: 10.1007/s10637-021-01089-3. Epub 2021 Mar 08.

Rapamycin synergizes the cytotoxic effects of MEK inhibitor binimetinib and overcomes acquired resistance to therapy in melanoma cell lines in vitro.

Investigational new drugs

Oxana O Ryabaya, Ivan S Abramov, Dmitry A Khochenkov, Roman Akasov, Nataly V Sholina, Anastasia A Prokofieva

Affiliations

  1. Department of the Experimental Diagnostic and Tumor Therapy N.N., Bloknin National Medical Research Center of Oncology, 24 Kashirskoe Shosse, Moscow, 115478, Russia. [email protected].
  2. Center of Strategical Planning, Moscow, Russia, 10-1 Pogodinskaya Street, Moscow, 119121, Russia.
  3. Department of the Experimental Diagnostic and Tumor Therapy N.N., Bloknin National Medical Research Center of Oncology, 24 Kashirskoe Shosse, Moscow, 115478, Russia.
  4. Togliatti State University, Belorusskaya str. 14, Togliatti, 445020, Russia.
  5. Institute of Molecular Medicine Sechenov First Moscow State Medical University, 8-2 Trubetskaya Street, Moscow, 119991, Russia.
  6. Department of Biomaterials and Biotechnologies, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia.
  7. Federal Scientific Research Center «Crystallography and Photonics», Russian Academy of Sciences, 17a Butlerova st, Moscow, 117997, Russia.

PMID: 33683500 DOI: 10.1007/s10637-021-01089-3

Abstract

Objective The problem of drug resistance to BRAF-targeted therapy often occurs in melanoma treatment. Activation of PI3K/AKT/mTOR signaling pathway is one of the mechanisms of acquired resistance and a potential target for treatment. In the current research, we investigated that dual inhibition of mTOR and MEK synergistically reduced the viability of melanoma cells in vitro. Methods A combination of rapamycin (a macrolide immunosuppressant, mTOR inhibitor) and binimetinib (an anti-cancer small molecule, selective inhibitor of MEK) was studied using a panel of melanoma cell lines, including patient-derived cells. Results It was found, that combinatorial therapy of rapamycin (250 nM) and binimetinib (2 μM) resulted in 25% of cell viability compared to either rapamycin (85%) or binimetinib alone (50%) for A375 and vemurafenib-resistant Mel IL/R cells. The suppressed activation of mTOR and MEK by combined rapamycin and binimetinib treatment was confirmed using Western blot assay. Cell death occured via the apoptosis pathway; however, the combination treatment significantly increased the apoptosis only for Mel IL/R cells. The enhanced cytotoxic effect was also associated with enhanced cell cycle arrest in the G0/G1 phase. Conclusion In general, we provide the evidence that dual inhibition of mTOR and MEK could be promising for further preclinical investigations.

© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Keywords: Acquired resistance; BRAFV600 melanoma cells; Binimetinib; Cutaneous melanoma; Rapamycin

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