Jonathan Thomas

Background: Uveal melanoma is the most common intraocular cancer in adults.¹ It is a form of cancer of the melanocytes in the uvea, which includes the iris, ciliary body, and choroid where most uveal melanomas are located.² Tumorigenesis usually occurs from a mutation in GNAQ and GNA11, which encode for G_aq and G_a11.^1-3 As a result of these mutations, MEK signaling will be increased.¹ While there is treatment for the primary tumor, the prognosis for metastasis of uveal melanoma is poor with death expected considering there is no treatment for metastasis.^1-4 MEK inhibitors were thought to provide a new way to treat uveal melanoma by inducing apoptosis, but clinical studies with sole MEK inhibitor treatment have not been effective due to resistance.^1,5

Objective: The purpose of this study is to examine the mechanisms driving current drug resistance in uveal melanoma, especially from the AKT pathway, to develop therapies to overcome resistance and prevent further negative effects from metastasis.

Search Methods: A search of the electronic database PubMed was made to identify peer-reviewed systematic reviews, mechanistic studies, and drug trials that evaluated drug resistance in uveal melanoma that were published between 2017-2023. The search terms utilized MeSH keywords and general keywords based on a combination of 2 concepts: 1) uveal melanoma and 2) MEK resistance. MeSH keywords included “ “Uveal Neoplasms”[Mesh]” and “ “Drug Resistance”[Mesh]” while keywords included uveal melanoma, drug resistance, MEK resistance, and other similar search strategies.

Results: Hepatocyte growth factor (HGF), human epidermal growth factor receptor 2 (HER2), and mevalonate all were found to confer drug resistance through the AKT pathway while histone deacetylase 11 (HDAC11) conferred drug resistance through YAP/TAZ signaling.^1,6-8 Specifically, in the presence of a MEK inhibitor, HGF restored S phase entry, reduced apoptosis, and increased AKT phosphorylation.¹ HER2 also increased AKT phosphorylation.⁶ Blockage of mevalonate through a statin significantly reduced cell growth.⁷ Lastly, silencing HDAC11 allowed for the apoptotic effects of MEK inhibition, which shows the role of HDAC11 in uveal melanoma drug resistance.⁸

Conclusion: Although drug therapy has been limited, the outlook is bright with possible co-treatment that targets the multiple resistance pathways in uveal melanoma. Newer studies need to note the efficacy of MEK inhibitors with co-treatment that targets a drug resistance pathway. However, these studies need to address several questions: specifically, will treatment need to rely on targeting multiple pathways involved in MEK inhibitor drug resistance? Further research and clinical trials are needed to see the effect of treatment of MEK inhibitors with one versus multiple pathways that are targeted.

Works Cited

1. Cheng H, Kageyama K, Purwin T, et al. Co-targeting HGF-cMET signaling with MEK inhibitors in metastatic uveal melanoma. Cancer Res. 2016;76(14_Supplement):4664.
2. Jager MJ, Shields CL, Cebulla CM, et al. Uveal melanoma. Nat Rev Dis Primers. 2020;6(1):24-0. doi: 10.1038/s41572-020-0158-0.
3. Smit KN, Jager MJ, de Klein A, Kiliҫ E. Uveal melanoma: Towards a molecular understanding. Prog Retin Eye Res. 2020;75:100800. doi: 10.1016/j.preteyeres.2019.100800.
4. Krantz BA, Dave N, Komatsubara KM, Marr BP, Carvajal RD. Uveal melanoma: Epidemiology, etiology, and treatment of primary disease. Clin Ophthalmol. 2017;11:279-289. doi: 10.2147/OPTH.S89591.
5. Khan S, Patel SP, Shoushtari AN, et al. Intermittent MEK inhibition for the treatment of metastatic uveal melanoma. Frontiers in Oncology. 2022;12.
6. Chen C, Hsia T, Yeh M, et al. MEK inhibitors induce akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER 2 phosphorylation at Thr701. Molecular oncology. 2017;11(9):1273-1287.
7. Iizuka-Ohashi M, Watanabe M, Sukeno M, et al. Blockage of the mevalonate pathway overcomes the apoptotic resistance to MEK inhibitors with suppressing the activation of akt in cancer cells. Oncotarget. 2018;9(28):19597.
8. Sriramareddy SN, Faião-Flores F, Emmons MF, et al. HDAC11 activity contributes to MEK inhibitor escape in uveal melanoma. Cancer Gene Ther. 2022:1-7.