Dual Inhibition of MEK and PI3K Pathway in KRAS and BRAF Mutated Colorectal Cancers

被引:87
作者
Temraz, Sally [1 ]
Mukherji, Deborah [1 ]
Shamseddine, Ali [1 ]
机构
[1] Amer Univ Beirut, Med Ctr, Div Hematol Oncol, Dept Internal Med, Beirut 110 72020, Lebanon
来源
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2015年 / 16卷 / 09期
关键词
colorectal cancer; drug resistance; phosphatidylinositol; 3-kinase; mitogen-activated protein kinase; MEK; TUMOR-GROWTH; AZD6244; ARRY-142886; PHASE-I; SELUMETINIB AZD6244; KINASE INHIBITORS; PIK3CA MUTATION; K-RAS; COMBINATION; RESISTANCE; PHOSPHORYLATION;
D O I
10.3390/ijms160922976
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Colorectal cancer (CRC) is a heterogeneous disease with multiple underlying causative genetic mutations. Genetic mutations in the phosphatidylinositol-3 kinase (PI3K) and the mitogen activated protein kinase (MAPK) pathways are frequently implicated in CRC. Targeting the downstream substrate MEK in these mutated tumors stands out as a potential target in CRC. Several selective inhibitors of MEK have entered clinical trial evaluation; however, clinical activity with single MEK inhibitors has been rarely observed and acquired resistance seems to be inevitable. Amplification of the driving oncogene KRAS(13D), which increases signaling through the ERK1/2 pathway, upregulation of the noncanonical wingless/calcium signaling pathway (Wnt), and coexisting PIK3CA mutations have all been implicated with resistance against MEK inhibitor therapy in KRAS mutated CRC. The Wnt pathway and amplification of the oncogene have also been associated with resistance to MEK inhibitors in CRCs harboring BRAF mutations. Thus, dual targeted inhibition of MEK and PI3K pathway effectors (mTOR, PI3K, AKT, IGF-1R or PI3K/mTOR inhibitors) presents a potential strategy to overcome resistance to MEK inhibitor therapy. Many clinical trials are underway to evaluate multiple combinations of these pathway inhibitors in solid tumors.
引用
收藏
页码:22976 / 22988
页数:13
相关论文
共 54 条
  • [1] Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERKI/2 signalling and/or strong P13K signalling in colorectal cancer cell lines
    Balmanno, Kathryn
    Chell, Simon D.
    Gillings, Annette S.
    Hayat, Shaista
    Cook, Simon J.
    [J]. INTERNATIONAL JOURNAL OF CANCER, 2009, 125 (10) : 2332 - 2341
  • [2] 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
  • [3] A Phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens
    Bennouna, Jaafar
    Lang, Istvan
    Valladares-Ayerbes, Manuel
    Boer, Katalin
    Adenis, Antoine
    Escudero, Pilar
    Kim, Tae-You
    Pover, Gillian M.
    Morris, Clive D.
    Douillard, Jean-Yves
    [J]. INVESTIGATIONAL NEW DRUGS, 2011, 29 (05) : 1021 - 1028
  • [4] Antitumor activities of ATP-competitive inhibitors of mTOR in colon cancer cells
    Blaser, Benjamin
    Waselle, Laurent
    Dormond-Meuwly, Anne
    Dufour, Marc
    Roulin, Didier
    Demartines, Nicolas
    Dormond, Olivier
    [J]. BMC CANCER, 2012, 12
  • [5] PI3K and MEK inhibitor combinations: examining the evidence in selected tumor types
    Britten, Carolyn D.
    [J]. CANCER CHEMOTHERAPY AND PHARMACOLOGY, 2013, 71 (06) : 1395 - 1409
  • [6] The PTEN-PI3K pathway: of feedbacks and cross-talks
    Carracedo, A.
    Pandolfi, P. P.
    [J]. ONCOGENE, 2008, 27 (41) : 5527 - 5541
  • [7] Mammalian MAP kinase signalling cascades
    Chang, LF
    Karin, M
    [J]. NATURE, 2001, 410 (6824) : 37 - 40
  • [8] Effect of BRAF V600E mutation on tumor response of anti-EGFR monoclonal antibodies for first-line metastatic colorectal cancer treatment: a meta-analysis of randomized studies
    Cui, Dandan
    Cao, Dan
    Yang, Yu
    Qiu, Meng
    Huang, Ying
    Yi, Cheng
    [J]. MOLECULAR BIOLOGY REPORTS, 2014, 41 (03) : 1291 - 1298
  • [9] AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases:: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models
    Davies, Barry R.
    Logie, Armelle
    McKay, Jennifer S.
    Martin, Paul
    Steele, Samantha
    Jenkins, Richard
    Cockerill, Mark
    Cartlidge, Sue
    Smith, Paul D.
    [J]. MOLECULAR CANCER THERAPEUTICS, 2007, 6 (08) : 2209 - 2219
  • [10] KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer
    De Roock, Wendy
    De Vriendt, Veerle
    Normanno, Nicola
    Ciardiello, Fortunato
    Tejpar, Sabine
    [J]. LANCET ONCOLOGY, 2011, 12 (06) : 594 - 603