MEK inhibitors: a new class of chemotherapeutic agents with ocular toxicity

被引:60
作者
Duncan, K. E. [1 ]
Chang, L. Y. [2 ]
Patronas, M. [1 ]
机构
[1] Univ Maryland, Sch Med, Dept Ophthalmol & Visual Sci, Baltimore, MD 21201 USA
[2] Univ Maryland, Sch Med, Baltimore, MD 21201 USA
关键词
DOSE-ESCALATION TRIAL; PHASE-I; AZD6244; ARRY-142886; ADVANCED CANCERS; MELANOMA; TRAMETINIB; 1ST-IN-HUMAN; THERAPY; PATHWAY; CI-1040;
D O I
10.1038/eye.2015.82
中图分类号
R77 [眼科学];
学科分类号
100212 ;
摘要
A new class of chemotherapeutic agents, MEK inhibitors, has recently been developed and is proving to be an effective treatment for a number of cancers. A pattern of ocular adverse events has followed these drugs through clinical trials and their association with retinopathy is only just beginning to be recognized. We present two cases of MEK inhibitor-associated retinopathy followed by a review of the current literature on ocular toxicity associated with MEK inhibitors. Patients undergoing treatment with MEK inhibitors appear to have high rates of multifocal serous retinal detachments as well as retinal vein occlusions. We present the first report of cystoid macular edema associated with MEK inhibitor use. The mechanism of these adverse events is still unclear though they seem to be related to oxidative stress and blood retinal barrier breakdown. Management of the ocular toxicity can range from observation to topical treatments or intravitreal injections. Fortunately most ocular adverse events appear to be self-limited and do not require discontinuing the MEK inhibitor. Discontinuation or decreased dosing of MEK inhibitors may be reserved for cases of severe sight-threatening ocular toxicity.
引用
收藏
页码:1003 / 1012
页数:10
相关论文
共 23 条
  • [1] Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers
    Adjei, Alex A.
    Cohen, Roger B.
    Franklin, Wilbur
    Morris, Clive
    Wilson, David
    Molina, Julian R.
    Hanson, Lorelei J.
    Gore, Lia
    Chow, Laura
    Leong, Stephen
    Maloney, Lara
    Gordon, Gilad
    Simmons, Heidi
    Marlow, Allison
    Litwiler, Kevin
    Brown, Suzy
    Poch, Gregory
    Kane, Katie
    Haney, Jerry
    Eckhardt, S. Gail
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (13) : 2139 - 2146
  • [2] MEK and the inhibitors: from bench to bedside
    Akinleye, Akintunde
    Furqan, Muhammad
    Mukhi, Nikhil
    Ravella, Pavan
    Liu, Delong
    [J]. JOURNAL OF HEMATOLOGY & ONCOLOGY, 2013, 6
  • [3] The First-in-Human Study of the Hydrogen Sulfate (Hyd-Sulfate) Capsule of the MEK1/2 Inhibitor AZD6244 (ARRY-142886): A Phase I Open-Label Multicenter Trial in Patients with Advanced Cancer
    Banerji, Udai
    Camidge, D. Ross
    Verheul, Henk M. W.
    Agarwal, Roshan
    Sarker, Debashis
    Kaye, Stan B.
    Desar, Ingrid M. E.
    Timmer-Bonte, Johanna N. H.
    Eckhardt, S. Gail
    Lewis, Karl D.
    Brown, Kathryn H.
    Cantarini, Mireille V.
    Morris, Clive
    George, Sarah M. A.
    Smith, Paul D.
    van Herpen, Carla M. L.
    [J]. CLINICAL CANCER RESEARCH, 2010, 16 (05) : 1613 - 1623
  • [4] Targeting MAPK pathway in melanoma therapy
    Cheng, Yabin
    Zhang, Guohong
    Li, Gang
    [J]. CANCER AND METASTASIS REVIEWS, 2013, 32 (3-4) : 567 - 584
  • [5] BRAF mutation in papillary thyroid carcinoma
    Cohen, J
    Xing, MZ
    Mambo, E
    Guo, ZM
    Wu, GG
    Trink, B
    Beller, U
    Westra, WH
    Ladenson, PW
    Sidransky, D
    [J]. JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2003, 95 (08) : 625 - 627
  • [6] Mutations of the BRAF gene in human cancer
    Davies, H
    Bignell, GR
    Cox, C
    Stephens, P
    Edkins, S
    Clegg, S
    Teague, J
    Woffendin, H
    Garnett, MJ
    Bottomley, W
    Davis, N
    Dicks, N
    Ewing, R
    Floyd, Y
    Gray, K
    Hall, S
    Hawes, R
    Hughes, J
    Kosmidou, V
    Menzies, A
    Mould, C
    Parker, A
    Stevens, C
    Watt, S
    Hooper, S
    Wilson, R
    Jayatilake, H
    Gusterson, BA
    Cooper, C
    Shipley, J
    Hargrave, D
    Pritchard-Jones, K
    Maitland, N
    Chenevix-Trench, G
    Riggins, GJ
    Bigner, DD
    Palmieri, G
    Cossu, A
    Flanagan, A
    Nicholson, A
    Ho, JWC
    Leung, SY
    Yuen, ST
    Weber, BL
    Siegler, HF
    Darrow, TL
    Paterson, H
    Marais, R
    Marshall, CJ
    Wooster, R
    [J]. NATURE, 2002, 417 (6892) : 949 - 954
  • [7] Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial
    Falchook, Gerald S.
    Lewis, Karl D.
    Infante, Jeffrey R.
    Gordon, Michael S.
    Vogelzang, Nicholas J.
    DeMarini, Douglas J.
    Sun, Peng
    Moy, Christopher
    Szabo, Stephen A.
    Roadcap, Lori T.
    Peddareddigari, Vijay G. R.
    Lebowitz, Peter F.
    Le, Ngocdiep T.
    Burris, Howard A., III
    Messersmith, Wells A.
    O'Dwyer, Peter J.
    Kim, Kevin B.
    Flaherty, Keith
    Bendell, Johanna C.
    Gonzalez, Rene
    Kurzrock, Razelle
    Fecher, Leslie A.
    [J]. LANCET ONCOLOGY, 2012, 13 (08) : 782 - 789
  • [8] Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma
    Flaherty, Keith T.
    Robert, Caroline
    Hersey, Peter
    Nathan, Paul
    Garbe, Claus
    Milhem, Mohammed
    Demidov, Lev V.
    Hassel, Jessica C.
    Rutkowski, Piotr
    Mohr, Peter
    Dummer, Reinhard
    Trefzer, Uwe
    Larkin, James M. G.
    Utikal, Jochen
    Dreno, Brigitte
    Nyakas, Marta
    Middleton, Mark R.
    Becker, Juergen C.
    Casey, Michelle
    Sherman, Laurie J.
    Wu, Frank S.
    Ouellet, Daniele
    Martin, Anne-Marie
    Patel, Kiran
    Schadendorf, Dirk
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2012, 367 (02) : 107 - 114
  • [9] PD0325901, a Mitogen-Activated Protein Kinase Kinase Inhibitor, Produces Ocular Toxicity in a Rabbit Animal Model of Retinal Vein Occlusion
    Huang, Wenhu
    Yang, Amy H.
    Matsumoto, Diane
    Collette, Walter
    Marroquin, Lisa
    Ko, Mira
    Aguirre, Shirley
    Younis, Husam S.
    [J]. JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS, 2009, 25 (06) : 519 - 530
  • [10] Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial
    Infante, Jeffrey R.
    Fecher, Leslie A.
    Falchook, Gerald S.
    Nallapareddy, Sujatha
    Gordon, Michael S.
    Becerra, Carlos
    DeMarini, Douglas J.
    Cox, Donna S.
    Xu, Yanmei
    Morris, Shannon R.
    Peddareddigari, Vijay G. R.
    Le, Ngocdiep T.
    Hart, Lowell
    Bendell, Johanna C.
    Eckhardt, Gail
    Kurzrock, Razelle
    Flaherty, Keith
    Burris, Howard A., III
    Messersmith, Wells A.
    [J]. LANCET ONCOLOGY, 2012, 13 (08) : 773 - 781