Skip to main content

Advertisement

SpringerLink
Log in

Belvarafenib penetrates the BBB and shows potent antitumor activity in a murine melanoma brain metastasis model

  • Research Paper
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

Brain metastasis is a common complication in melanoma patients with BRAF and NRAS mutations and has a poor prognosis. Although BRAF inhibitors are clinically approved, their poor brain penetration limits their efficacy in brain metastasis. Thus, melanoma brain metastasis still requires better treatment. Belvarafenib, a pan-RAF inhibitor, has reported antitumor activity in melanoma with RAF and RAS mutations in animal models and patients. However, brain permeability and antitumor efficacy on brain metastasis have not been determined. This study confirmed the brain penetration of belvarafenib, the antitumor activity on BRAF and NRAS mutant melanoma, and the efficacy on melanoma within the brain. Belvarafenib strongly suppressed melanoma in BRAF V600E mutant A375SM tumor-bearing mice. It also significantly inhibited tumor growth in NRAS mutant SK-MEL-30 and K1735 tumor-bearing mice and synergized to enhance the antitumor activity combined with cobimetinib or atezolizumab. Belvarafenib was penetrated at considerable levels into the brains of mice and rats following oral administration. The exposure of belvarafenib in the brain was similar to or higher than that in plasma, and this high brain penetration differed significantly from that of other BRAF inhibitors with low brain penetration. Most importantly, belvarafenib strongly reduced tumor burden and markedly improved survival benefits in mice intracranially implanted with A375SM melanoma. These results demonstrated that belvarafenib, which has favorable BBB permeability, and potent antitumor activity on the tumors with BRAF/NRAS mutations, may be a promising therapeutic option for patients with BRAF/NRAS mutant melanoma brain metastasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. National Institutes of Health (2022) Cancer Stat Facts: brain and other nervous system cancer. The website for the surveillance, epidemiology, and end results program at the national cancer. https://seer.cancer.gov/statfacts/html/brain.html Accessed 13 May 2022

  2. Faulkner C, Patricia HE, Shaw A et al (2015) BRAF fusion analysis in pilocytic astrocytomas: KIAA1549-BRAF 15–9 fusions are more frequent in the midline than within the cerebellum. J Neuropathol Exp Neurol 74(9):867–872. https://doi.org/10.1097/NEN.0000000000000226

    Article  CAS  PubMed  Google Scholar 

  3. Penman CL, Faulkner C, Lowis SP, Kurian KM (2015) Current understanding of BRAF alterations in diagnosis, prognosis, and therapeutic targeting in pediatric low-grade gliomas. Front Oncol 5:54. https://doi.org/10.3389/fonc.2015.00054

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kurani H, Gurav M, Shetty O, Chinnaswamy G et al (2019) Pilocytic astrocytomas: BRAFV600E and BRAF fusion expression patterns in pediatric and adult age groups. Childs Nerv Syst 35(9):1525–1536. https://doi.org/10.1007/s00381-019-04282-1

    Article  PubMed  Google Scholar 

  5. Ascierto PA, Kirkwood JM, Grob JJ et al (2012) The role of BRAF V600 mutation in melanoma. J Transl Med 10:85. https://doi.org/10.1186/1479-5876-10-85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lee JH, Choi JW, Kim YS (2010) Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol 164(4):776–784. https://doi.org/10.1111/j.1365-2133.2010.10185.x

    Article  CAS  Google Scholar 

  7. Yen I, Shanahan F, Lee J et al (2021) ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma. Nature 594:418–423. https://doi.org/10.1038/s41586-021-03515-1

    Article  CAS  PubMed  Google Scholar 

  8. Peng SB, Henry JR, Kaufman MD et al (2015) Inhibition of RAF isoforms and active dimers by LY3009120 leads to anti-tumor activities in RAS or BRAF mutant cancers. Cancer Cell 28:384–398. https://doi.org/10.1016/j.ccell.2015.08.002

    Article  CAS  PubMed  Google Scholar 

  9. Ramurthy S, Taft BR, Aversa RJ et al (2020) Design and discovery of N-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a selective, efficacious, and well-tolerated RAF inhibitor targeting RAS mutant cancers: the path to the clinic. J Med Chem 63:2013–2027. https://doi.org/10.1021/acs.jmedchem.9b00161

    Article  CAS  PubMed  Google Scholar 

  10. Makawita S, Tawbi HA (2021) Nonsurgical management of melanoma brain metastasis: current therapeutics, challenges, and strategies for progress. 2021 ASCO Educational book 41:79–90. https://doi.org/10.1200/EDBK_321137

    Article  PubMed  Google Scholar 

  11. Bouche V, Aldegheri G, Antonio C (2021) BRAF signaling inhibition in glioblastoma: which clinical perspectives? Front Oncol 11:772052. https://doi.org/10.3389/fonc.2021.772052

    Article  PubMed  PubMed Central  Google Scholar 

  12. Knobbe CB, Reifenberger J, Reifenberger G (2004) Mutation analysis of the Ras pathway genes NRAS, HRAS, KRAS and BRAF in glioblastomas. Acta Neuropathol 108(6):467–470. https://doi.org/10.1007/s00401-004-0929-9

    Article  CAS  PubMed  Google Scholar 

  13. Wolfgang L, Heidrun P (2005) Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx 2(1):86–98. https://doi.org/10.1602/neurorx.2.1.86

    Article  Google Scholar 

  14. Eurydice A, Thuy TN, Anne J, Guilhem B (2020) How to make anticancer drugs cross the blood–brain barrier to treat brain metastases. Int J Mol Sci 21(1):22. https://doi.org/10.3390/ijms21010022

    Article  CAS  Google Scholar 

  15. Pardridge WM (2005) The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2(1):3–14. https://doi.org/10.1602/neurorx.2.1.3

    Article  PubMed  PubMed Central  Google Scholar 

  16. JingWang CG, Rolf WS et al (2018) P-glycoprotein (MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) affect brain accumulation and intestinal disposition of encorafenib in mice. Pharmacol Res 129:414–423. https://doi.org/10.1016/j.phrs.2017.11.006

    Article  CAS  Google Scholar 

  17. Rajendar KM, Shruthi V, Ramola S, William FE (2012) Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: vemurafenib (PLX4032). J Pharmacol Exp Ther 342(1):33–40. https://doi.org/10.1124/jpet.112.192195

    Article  CAS  Google Scholar 

  18. Rajendar KM, Shruthi V, Arkadiusz ZD, William FE (2013) Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther 344(3):655–664. https://doi.org/10.1124/jpet.112.201475

    Article  CAS  Google Scholar 

  19. Mittapalli RK, Vaidhyanathan S, Dudek AZ et al (2013) Mechanisms limiting distribution of the threonine-protein kinase B-RAF V600E inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. J Pharmacol Exp Ther 344:655–664. https://doi.org/10.1124/jpet.112.201475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bailleux C, Eberst L, Bachelot T (2021) Treatment strategies for breast cancer brain metastases. Br J Cancer 124:142–155. https://doi.org/10.1038/s41416-020-01175-y

    Article  PubMed  Google Scholar 

  21. Chamberlain MC, Baik CS, Gadi VK et al (2017) Systemic therapy of brain metastases: non–small cell lung cancer, breast cancer, and melanoma. Neuro Oncol 19(1):i1–i24. https://doi.org/10.1093/neuonc/now197

    Article  CAS  PubMed  Google Scholar 

  22. Kourtney H, Jose L et al (2020) Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: a case series. Cancer 126(3):523–530. https://doi.org/10.1002/cncr.32547

    Article  CAS  Google Scholar 

  23. Anna SB, Matthias P (2017) Targeted therapies for melanoma brain metastases. Curr Treat Options Neurol 19(4):13. https://doi.org/10.1093/noajnl/vdab131

    Article  Google Scholar 

  24. Teresa A, Felix K et al (2020) Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG study in 380 patients. J Immunother Cancer 8(1):e000333. https://doi.org/10.1136/jitc-2019-000333

    Article  Google Scholar 

  25. Anna MDG, Monica V et al (2019) Immunotherapy of brain metastases: breaking a “dogma.” J Exp Clin Cancer Res 38(1):419. https://doi.org/10.1186/s13046-019-1426-2

    Article  Google Scholar 

  26. Broman KK, Dossett LA, Sun J et al (2019) Update on BRAF and MEK inhibition for treatment of melanoma in metastatic, unresectable, and adjuvant settings. Expert Opin Drug Saf 18(5):381–392. https://doi.org/10.1080/14740338.2019.1607289

    Article  PubMed  Google Scholar 

  27. Kushnirsky M, Feun LG, Gultekin SH et al (2020) Prolonged complete response with combined dabrafenib and trametinib after BRAF inhibitor failure in BRAF-mutant glioblastoma. JCO Precis Oncol 4:44–50. https://doi.org/10.1200/PO.19.00272

    Article  Google Scholar 

  28. Gampa G, Vaidhyanathan S, Sarkaria JN, Elmquista WF (2018) Drug delivery to melanoma brain metastases: can current challenges lead to new opportunities? Pharmacol Res 123:10–25. https://doi.org/10.1016/j.phrs.2017.06.008

    Article  CAS  Google Scholar 

  29. Chen L, Zeng D, Xu N et al (2019) Blood–brain barrier- and blood–brain tumor barrier-penetrating peptide-derived targeted therapeutics for glioma and malignant tumor brain metastases. ACS Appl Mater Interfaces 45:41889–41897. https://doi.org/10.1021/acsami.9b14046

    Article  CAS  Google Scholar 

  30. Bae I, Kim YY et al (2021) Antitumor activity of belvarafenib in melanoma brain metastasis and NRAS mutation melanoma models. Cancer Res 81(13):1474. https://doi.org/10.1158/1538-7445.AM2021-1474

    Article  Google Scholar 

  31. Shin SJ, Lee J, Kim TM et al (2021) A phase Ib trial of belvarafenib in combination with cobimetinib in patients with advanced solid tumors: Interim results of dose-escalation and patients with NRAS-mutant melanoma of dose-expansion (Clinical trial: NCT03284502). J Clin Oncol 39(15):3007–3007. https://doi.org/10.1200/JCO.2021.39.15_suppl.3007

    Article  Google Scholar 

  32. Aya MK, Matthew RB, Sarah ZT et al (2022) Target-agnostic P-glycoprotein assessment yields strategies to evade efflux, leading to a BRAF inhibitor with intracranial efficacy. J Am Chem Soc 144(27):12367–12380. https://doi.org/10.1021/jacs.2c03944

    Article  CAS  Google Scholar 

  33. Lauritz M, Manuel V (2021) Animal models of brain metastasis. Neurooncol Adv 3(5):v144–v156. https://doi.org/10.1093/noajnl/vdab115

    Article  Google Scholar 

Download references

Author information

Author notes

  1. Yu-Yon Kim and Hyunjin Park have contributed equally.

Authors and Affiliations

  1. Hanmi Research Center, Hanmi Pharm. Co. Ltd, Gyeonggi-Do, Korea

    Yu-Yon Kim, Hyunjin Park, Taehun Song, Kyungjin Choi, Jisook Kim, Young Gil Ahn, Kwee Hyun Suh & Young Hoon Kim

  2. Genentech Inc, South San Francisco, CA, USA

    Michael Dolton & Jialin Mao

Authors
  1. Yu-Yon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyunjin Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Taehun Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyungjin Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Dolton
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jialin Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jisook Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Young Gil Ahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kwee Hyun Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Young Hoon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y-YK and HP wrote the main manuscript text and prepared figures 2, 3, 7, and 8, and TS and KC prepared figures 4, 5, and 6. JK synthesized test articles. All authors reviewed the manuscript.

Corresponding author

Correspondence to Young Hoon Kim.

Ethics declarations

Conflict of interest

The authors declare that there are no conflict of interest or financial ties regarding the publication of this article.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, YY., Park, H., Song, T. et al. Belvarafenib penetrates the BBB and shows potent antitumor activity in a murine melanoma brain metastasis model. Clin Exp Metastasis 40, 137–148 (2023). https://doi.org/10.1007/s10585-023-10198-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-023-10198-7

Keywords

Search

Navigation