Treatment of NRAS-mutant Melanoma

Overview

Journal Curr Treat Options Oncol

Specialty Oncology

Date 2015 Mar 23

PMID 25796376

Citations 69

Authors

Douglas B Johnson

Igor Puzanov

Affiliations

Soon will be listed here.

Abstract

NRAS mutations in codons 12, 13, and 61 arise in 15-20 % of all melanomas. These alterations have been associated with aggressive clinical behavior and a poor prognosis. Until recently, there has been a paucity of promising genetically targeted therapy approaches for NRAS-mutant melanoma (and RAS-mutant malignancies in general). MEK inhibitors, particularly binimetinib, have shown activity in this cohort. Based on pre-clinical and early clinical studies, combining MEK inhibitors with agents inhibiting the cell cycling and the PI3K-AKT pathway appears to provide additional benefit. In particular, a strategy of MEK inhibition and CDK4/6 inhibition is likely to be a viable treatment option in the future, and is the most promising genetically targeted treatment strategy for NRAS-mutant melanoma developed to date. In addition, immune-based therapies have shown increasing activity in advanced melanoma and may be particularly effective in those with NRAS mutations. Combination strategies of immune and targeted therapies may also play a role in the future although clinical trials testing these approaches are in early stages.

Citing Articles

Exploring the Common Mutational Landscape in Cutaneous Melanoma and Pancreatic Cancer.

Broseghini E, Venturi F, Veronesi G, Scotti B, Migliori M, Marini D Pigment Cell Melanoma Res. 2024; 38(1):e13210.

PMID: 39609109 PMC: 11681848. DOI: 10.1111/pcmr.13210.

IκBα kinase inhibitor BAY 11-7082 promotes anti-tumor effect in RAS-driven cancers.

Guruvaiah P, Gupta R J Transl Med. 2024; 22(1):642.

PMID: 38982514 PMC: 11233160. DOI: 10.1186/s12967-024-05384-4.

Isomer-sourced structure iteration methods for development of inhibitors: Inducing GTP-bound NRAS-Q61 oncogenic mutations to an "off-like" state.

Hu Z, Marti J Comput Struct Biotechnol J. 2024; 23:2418-2428.

PMID: 38882681 PMC: 11176632. DOI: 10.1016/j.csbj.2024.05.038.

The Pan-RAF-MEK Nondegrading Molecular Glue NST-628 Is a Potent and Brain-Penetrant Inhibitor of the RAS-MAPK Pathway with Activity across Diverse RAS- and RAF-Driven Cancers.

Ryan M, Quade B, Schenk N, Fang Z, Zingg M, Cohen S Cancer Discov. 2024; 14(7):1190-1205.

PMID: 38588399 PMC: 11215411. DOI: 10.1158/2159-8290.CD-24-0139.

Consistency between Primary Uterine Corpus Malignancies and Their Corresponding Patient-Derived Xenograft Models.

Ueda S, Tanaka T, Hirosuna K, Miyamoto S, Murakami H, Nishie R Int J Mol Sci. 2024; 25(3).

PMID: 38338763 PMC: 10855170. DOI: 10.3390/ijms25031486.

References

Su Y, Vilgelm A, Kelley M, Hawkins O, Liu Y, Boyd K . RAF265 inhibits the growth of advanced human melanoma tumors. Clin Cancer Res. 2012; 18(8):2184-98. PMC: 3724517. DOI: 10.1158/1078-0432.CCR-11-1122. View

Lovly C, Dahlman K, Fohn L, Su Z, Dias-Santagata D, Hicks D . Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials. PLoS One. 2012; 7(4):e35309. PMC: 3335021. DOI: 10.1371/journal.pone.0035309. View

Topalian S, Hodi F, Brahmer J, Gettinger S, Smith D, Mcdermott D . Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012; 366(26):2443-54. PMC: 3544539. DOI: 10.1056/NEJMoa1200690. View

Flaherty K, Robert C, Hersey P, Nathan P, Garbe C, Milhem M . Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012; 367(2):107-14. DOI: 10.1056/NEJMoa1203421. View

Hodis E, Watson I, Kryukov G, Arold S, Imielinski M, Theurillat J . A landscape of driver mutations in melanoma. Cell. 2012; 150(2):251-63. PMC: 3600117. DOI: 10.1016/j.cell.2012.06.024. View

Hauschild A, Grob J, Demidov L, Jouary T, Gutzmer R, Millward M . Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012; 380(9839):358-65. DOI: 10.1016/S0140-6736(12)60868-X. View

Falchook G, Lewis K, Infante J, Gordon M, Vogelzang N, Demarini D . Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012; 13(8):782-9. PMC: 4109286. DOI: 10.1016/S1470-2045(12)70269-3. View

Jakob J, Bassett Jr R, Ng C, Curry J, Joseph R, Alvarado G . NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2011; 118(16):4014-23. PMC: 3310961. DOI: 10.1002/cncr.26724. View

Krauthammer M, Kong Y, Ha B, Evans P, Bacchiocchi A, McCusker J . Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet. 2012; 44(9):1006-14. PMC: 3432702. DOI: 10.1038/ng.2359. View

10.

Haarberg H, Paraiso K, Wood E, Rebecca V, Sondak V, Koomen J . Inhibition of Wee1, AKT, and CDK4 underlies the efficacy of the HSP90 inhibitor XL888 in an in vivo model of NRAS-mutant melanoma. Mol Cancer Ther. 2013; 12(6):901-12. PMC: 3683468. DOI: 10.1158/1535-7163.MCT-12-1003. View

11.

Fedorenko I, Gibney G, Smalley K . NRAS mutant melanoma: biological behavior and future strategies for therapeutic management. Oncogene. 2012; 32(25):3009-18. PMC: 3978385. DOI: 10.1038/onc.2012.453. View

12.

Robert C, Dummer R, Gutzmer R, Lorigan P, Kim K, Nyakas M . Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study. Lancet Oncol. 2013; 14(8):733-40. DOI: 10.1016/S1470-2045(13)70237-7. View

13.

Imielinski M, Berger A, Hammerman P, Hernandez B, Pugh T, Hodis E . Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 2012; 150(6):1107-20. PMC: 3557932. DOI: 10.1016/j.cell.2012.08.029. View

14.

Kwong L, Costello J, Liu H, Jiang S, Helms T, Langsdorf A . Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med. 2012; 18(10):1503-10. PMC: 3777533. DOI: 10.1038/nm.2941. View

15.

Conrad W, Swift R, Biechele T, Kulikauskas R, Moon R, Chien A . Regulating the response to targeted MEK inhibition in melanoma: enhancing apoptosis in NRAS- and BRAF-mutant melanoma cells with Wnt/β-catenin activation. Cell Cycle. 2012; 11(20):3724-30. PMC: 3495814. DOI: 10.4161/cc.21645. View

16.

Flaherty K, Infante J, Daud A, Gonzalez R, Kefford R, Sosman J . Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012; 367(18):1694-703. PMC: 3549295. DOI: 10.1056/NEJMoa1210093. View

17.

Feng Y, Lau E, Scortegagna M, Ruller C, K DE S, Barile E . Inhibition of melanoma development in the Nras((Q61K)) ::Ink4a(-/-) mouse model by the small molecule BI-69A11. Pigment Cell Melanoma Res. 2012; 26(1):136-42. PMC: 3632643. DOI: 10.1111/pcmr.12033. View

18.

Gajewski T, Salama A, Niedzwiecki D, Johnson J, Linette G, Bucher C . Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104). J Transl Med. 2012; 10:246. PMC: 3543225. DOI: 10.1186/1479-5876-10-246. View

19.

Ascierto P, Schadendorf D, Berking C, Agarwala S, van Herpen C, Queirolo P . MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013; 14(3):249-56. DOI: 10.1016/S1470-2045(13)70024-X. View

20.

Posch C, Moslehi H, Feeney L, Green G, Ebaee A, Feichtenschlager V . Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo. Proc Natl Acad Sci U S A. 2013; 110(10):4015-20. PMC: 3593920. DOI: 10.1073/pnas.1216013110. View