binimetinib and sotrastaurin

To analyze the clinical characteristics of a serous retinopathy associated with mitogen-activated protein kinase kinase (MEK) inhibition with binimetinib treatment for metastatic cutaneous melanoma (CM) and uveal melanoma (UM), and to determine possible pathogenetic mechanisms that may lead to this retinopathy.. Prospective observational, cohort-based, cross-sectional study.. Thirty CM patients and 5 UM patients treated with the MEK inhibitor binimetinib (CM) or a combination of binimetinib and the protein kinase C inhibitor sotrastaurin (UM).. Extensive ophthalmic examination was performed, including Early Treatment of Diabetic Retinopathy Study best-corrected visual acuity, applanation tonometry, slit-lamp examination, indirect ophthalmoscopy, digital color fundus photography, and optical coherence tomography (OCT). In selected cases, additional examinations were performed, including visual field testing and electro-oculography (EOG). Blood samples were obtained from 3 CM patients and 3 UM patients to analyze the presence of autoantibodies against retinal and retinal pigment epithelium (RPE) proteins.. Visual symptoms, visual acuity, fundus appearance, characteristics on OCT, fundus autofluorescence (FAF), and EOG.. Six CM patients (20%) and 2 UM patients (40%) reported visual symptoms during the study. The median time to the onset of symptoms, which were all mild and transient, was 3.5 days (range, <1 hour to 3 weeks). On OCT, subretinal fluid (SRF) was detected in 77% of CM patients and 60% of UM patients. In the 26 patients with SRF, the fovea was affected in 85%. After the start of the medication, an EOG was performed in 19 eyes of 11 patients; 16 of these eyes (84%) developed SRF on OCT. Fifteen of these eyes (94%) showed an abnormal Arden ratio (<1.65). A broad pattern of anti-retinal antibodies was found in 3 CM patients and 2 UM patients tested, whereas anti-RPE antibodies were detected in all 6 tested patients.. A time-dependent and reversible serous retinopathy can develop both in patients with metastatic CM and UM treated with binimetinib. A minority of patients develop visual symptoms, which are generally mild and transient. A cause of binimetinib-associated serous retinopathy may be toxicity of medication, but autoantibodies also may be involved.

Topics: Adult; Aged; Autoantibodies; Benzimidazoles; Central Serous Chorioretinopathy; Cross-Sectional Studies; Drug Combinations; Electrooculography; Electroretinography; Eye Proteins; Female; Fluorescein Angiography; Humans; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Prospective Studies; Protein Kinase C; Pyrroles; Quinazolines; Skin Neoplasms; Subretinal Fluid; Tomography, Optical Coherence; Uveal Neoplasms; Visual Acuity

Uveal melanoma (UM) is a genetically and biologically distinct type of melanoma, and once metastatic there is no effective treatment currently available. Eighty percent of UMs harbor mutations in the Gαq family members GNAQ and GNA11. Understanding the effector pathways downstream of these oncoproteins is important to identify opportunities for targeted therapy. We report consistent activation of the protein kinase C (PKC) and MAPK pathways as a consequence of GNAQ or GNA11 mutation. PKC inhibition with AEB071 or AHT956 suppressed PKC and MAPK signalling and induced G1 arrest selectively in melanoma cell lines carrying GNAQ or GNA11 mutations. In contrast, treatment with two different MEK inhibitors, PD0325901 and MEK162, inhibited the proliferation of melanoma cell lines irrespective of their mutation status, indicating that in the context of GNAQ or GNA11 mutation MAPK activation can be attributed to activated PKC. AEB071 significantly slowed the growth of tumors in an allograft model of GNAQ(Q209L)-transduced melanocytes, but did not induce tumor shrinkage. In vivo and in vitro studies showed that PKC inhibitors alone were unable to induce sustained suppression of MAP-kinase signaling. However, combinations of PKC and MEK inhibition, using either PD0325901or MEK162, led to sustained MAP-kinase pathway inhibition and showed a strong synergistic effect in halting proliferation and in inducing apoptosis in vitro. Furthermore, combining PKC and MEK inhibition was efficacious in vivo, causing marked tumor regression in a UM xenograft model. Our data identify PKC as a rational therapeutic target for melanoma patients with GNAQ or GNA11 mutations and demonstrate that combined MEK and PKC inhibition is synergistic, with superior efficacy compared to treatment with either approach alone.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Female; GTP-Binding Protein alpha Subunits; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Inhibitory Concentration 50; MAP Kinase Kinase Kinases; Melanoma; Mice; Mice, Inbred C57BL; Mice, Nude; Mutation, Missense; Protein Kinase C; Protein Kinase Inhibitors; Pyrroles; Quinazolines; Signal Transduction; Tumor Burden; Uveal Neoplasms; Xenograft Model Antitumor Assays