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
  • [11] Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis
    De Roock, Wendy
    Claes, Bart
    Bernasconi, David
    De Schutter, Jef
    Biesmans, Bart
    Fountzilas, George
    Kalogeras, Konstantine T.
    Kotoula, Vassiliki
    Papamichael, Demetris
    Laurent-Puig, Pierre
    Penault-Llorca, Frederique
    Rougier, Philippe
    Vincenzi, Bruno
    Santini, Daniele
    Tonini, Giuseppe
    Cappuzzo, Federico
    Frattini, Milo
    Molinari, Francesca
    Saletti, Piercarlo
    De Dosso, Sara
    Martini, Miriam
    Bardelli, Alberto
    Siena, Salvatore
    Sartore-Bianchi, Andrea
    Tabernero, Josep
    Macarulla, Teresa
    Di Fiore, Frederic
    Gangloff, Alice Oden
    Ciardiello, Fortunato
    Pfeiffer, Per
    Qvortrup, Camilla
    Hansen, Tine Plato
    Van Cutsem, Eric
    Piessevaux, Hubert
    Lambrechts, Diether
    Delorenzi, Mauro
    Tejpar, Sabine
    [J]. LANCET ONCOLOGY, 2010, 11 (08) : 753 - 762
  • [12] Combine MEK inhibition with PI3K/mTOR inhibition exert inhibitory tumor growth effect on KRAS and PIK3CA mutation CRC xenografts due to reduced expression of VEGF and matrix metallopeptidase-9
    E, Jifu
    Xing, Junjie
    Gong, Haifeng
    He, Jian
    Zhang, Wei
    [J]. TUMOR BIOLOGY, 2015, 36 (02) : 1091 - 1097
  • [13] Overcoming IGF1R/IR Resistance through Inhibition of MEK Signaling in Colorectal Cancer Models
    Flanigan, Sara A.
    Pitts, Todd M.
    Newton, Timothy P.
    Kulikowski, Gillian N.
    Tan, Aik Choon
    McManus, Martine C.
    Spreafico, Anna
    Kachaeva, Maria I.
    Selby, Heather M.
    Tentler, John J.
    Eckhardt, S. Gail
    Leong, Stephen
    [J]. CLINICAL CANCER RESEARCH, 2013, 19 (22) : 6219 - 6229
  • [14] From basic research to clinical development of MEK1/2 inhibitors for cancer therapy
    Fremin, Christophe
    Meloche, Sylvain
    [J]. JOURNAL OF HEMATOLOGY & ONCOLOGY, 2010, 3
  • [15] The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition
    Haagensen, E. J.
    Kyle, S.
    Beale, G. S.
    Maxwell, R. J.
    Newell, D. R.
    [J]. BRITISH JOURNAL OF CANCER, 2012, 106 (08) : 1386 - 1394
  • [16] PIK3CA Mutation Uncouples Tumor Growth and Cyclin D1 Regulation from MEK/ERK and Mutant KRAS Signaling
    Halilovic, Ensar
    She, Qing-Bai
    Ye, Qing
    Pagliarini, Raymond
    Sellers, William R.
    Solit, David B.
    Rosen, Neal
    [J]. CANCER RESEARCH, 2010, 70 (17) : 6804 - 6814
  • [17] Intermittent Administration of MEK Inhibitor GDC-0973 plus PI3K Inhibitor GDC-0941 Triggers Robust Apoptosis and Tumor Growth Inhibition
    Hoeflich, Klaus P.
    Merchant, Mark
    Orr, Christine
    Chan, Jocelyn
    Den Otter, Doug
    Berry, Leanne
    Kasman, Ian
    Koeppen, Hartmut
    Rice, Ken
    Yang, Nai-Ying
    Engst, Stefan
    Johnston, Stuart
    Friedman, Lori S.
    Belvin, Marcia
    [J]. CANCER RESEARCH, 2012, 72 (01) : 210 - 219
  • [18] Enhanced Apoptosis and Tumor Growth Suppression Elicited by Combination of MEK (Selumetinib) and mTOR Kinase Inhibitors (AZD8055)
    Holt, Sarah V.
    Logie, Armelle
    Davies, Barry R.
    Alferez, Denis
    Runswick, Sarah
    Fenton, Sarah
    Chresta, Christine M.
    Gu, Yi
    Zhang, Jingchuan
    Wu, Yi-Long
    Wilkinson, Robert W.
    Guichard, Sylvie M.
    Smith, Paul D.
    [J]. CANCER RESEARCH, 2012, 72 (07) : 1804 - 1813
  • [19] Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling
    Ikenoue, Tsuneo
    Inoki, Ken
    Yang, Qian
    Zhou, Xiaoming
    Guan, Kun-Liang
    [J]. EMBO JOURNAL, 2008, 27 (14) : 1919 - 1931
  • [20] PIK3CA Mutations in Patients with Advanced Cancers Treated with PI3K/AKT/mTOR Axis Inhibitors
    Janku, Filip
    Tsimberidou, Apostolia M.
    Garrido-Laguna, Ignacio
    Wang, Xuemei
    Luthra, Rajyalakshmi
    Hong, David S.
    Naing, Aung
    Falchook, Gerald S.
    Moroney, John W.
    Piha-Paul, Sarina A.
    Wheler, Jennifer J.
    Moulder, Stacy L.
    Fu, Siqing
    Kurzrock, Razelle
    [J]. MOLECULAR CANCER THERAPEUTICS, 2011, 10 (03) : 558 - 565