MEK Inhibitor-Associated Ocular Hypertension

Abstract

Introduction: Mitogen-activated protein kinase kinase (MEK) inhibitors are targeted anticancer agents that are prescribed to treat a broad range of cancers. Despite their strong efficacy profile, MEK inhibitors have been associated with ocular toxicities, most notably, self-limited serous detachments of the neurosensory retina. In this report, we outline 3 cases of a rarely documented toxicity, MEK inhibitor-associated ocular hypertension.

Case presentations: In the first case, a 69-year-old female with metastatic cholangiocarcinoma presented with an intraocular pressure (IOP) of 25 mm Hg right eye (OD) and 27 mm Hg left eye (OS) 2 months after starting trametinib therapy. Similarly, in the second case, a 26-year-old female with Langerhans cell histiocytosis presented with an elevated IOP of 24 mm Hg bilaterally (OU) 13 months after beginning treatment with an investigational MEK inhibitor. In the third case, a 46-year-old male with Langerhans cell histiocytosis presented with a new onset of elevated IOP of 24 mm Hg 21 days after initiating treatment with cobimetinib. All 3 patients' IOP returned to normal following dorzolamide/timolol administration and continued their cancer therapy.

Discussion/conclusion: This report presents 3 cases of elevated IOP in patients taking three distinct MEK inhibitors which would suggest that IOP-elevating effects exist across the class of MEK inhibitors. All 3 patients had a satisfactory response to topical pressure-lowering drops while continuing their life-preserving MEK inhibitor drug dose, indicating that discontinuation of therapy may not be necessary. Due to the increasing use of MEK inhibitors, it is important that ophthalmologists familiarize themselves with the broad range of potential adverse ocular effects of MEK inhibitors.

Keywords: Drug toxicity; Ocular hypertension; Oncology.

Fig. 1.

MEK inhibitor effect on transforming growth factor-β (TGF-β) signaling pathways. TGF-β binds to its TGF-β receptors, triggering autophosphorylation of the tyrosine residue in the TGF-β receptor II. In turn, Src homology domain 2-containing protein (Shc), growth factor receptor-binding protein 2 (Grb2), and SOS are recruited. SOS, a GEF, then activates RAS and RAC1. RAS can activate RAF which triggers the activation of MEK 1 and subsequently ERK 1/2. During MEK inhibition, MEK 1 will not activate ERK 1/2, leading to the inactivation of the RAS/RAF/MEK/ERK pathway and inhibition of expression of plasminogen activator inhibitor-1 (PAI-1). RAC1, however, can still activate CLAN as well as p21-activated kinase (PAK), MAP kinase kinase (MKK) 3/6, and P38. This pathway may be upregulated. P38 crosses the nucleus and induces the expression of IL-6 and SPARC. CLAN, cross-linked actin network.