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
  • [41] Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
    Sarbassov, DD
    Guertin, DA
    Ali, SM
    Sabatini, DM
    [J]. SCIENCE, 2005, 307 (5712) : 1098 - 1101
  • [42] The Clinical Effect of the Dual-Targeting Strategy Involving PI3K/AKT/mTOR and RAS/MEK/ERK Pathways in Patients with Advanced Cancer
    Shimizu, Toshio
    Tolcher, Anthony W.
    Papadopoulos, Kyriakos P.
    Beeram, Muralidhar
    Rasco, Drew W.
    Smith, Lon S.
    Gunn, Shelly
    Smetzer, Leslie
    Mays, Theresa A.
    Kaiser, Brianne
    Wick, Michael J.
    Alvarez, Cathy
    Cavazos, Aracely
    Mangold, Gina L.
    Patnaik, Amita
    [J]. CLINICAL CANCER RESEARCH, 2012, 18 (08) : 2316 - 2325
  • [43] BRAF mutation predicts sensitivity to MEK inhibition
    Solit, DB
    Garraway, LA
    Pratilas, CA
    Sawai, A
    Getz, G
    Basso, A
    Ye, Q
    Lobo, JM
    She, YH
    Osman, I
    Golub, TR
    Sebolt-Leopold, J
    Sellers, WR
    Rosen, N
    [J]. NATURE, 2006, 439 (7074) : 358 - 362
  • [44] Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials
    Sorich, M. J.
    Wiese, M. D.
    Rowland, A.
    Kichenadasse, G.
    McKinnon, R. A.
    Karapetis, C. S.
    [J]. ANNALS OF ONCOLOGY, 2015, 26 (01) : 13 - 21
  • [45] Rational Combination of a MEK Inhibitor, Selumetinib, and the Wnt/Calcium Pathway Modulator, Cyclosporin A, in Preclinical Models of Colorectal Cancer
    Spreafico, Anna
    Tentler, John J.
    Pitts, Todd M.
    Tan, Aik Choon
    Gregory, Mark A.
    Arcaroli, John J.
    Klauck, Peter J.
    McManus, Martine C.
    Hansen, Ryan J.
    Kim, Jihye
    Micel, Lindsey N.
    Selby, Heather M.
    Newton, Timothy P.
    McPhillips, Kelly L.
    Gustafson, Daniel L.
    DeGregori, James V.
    Messersmith, Wells A.
    Winn, Robert A.
    Eckhardt, S. Gail
    [J]. CLINICAL CANCER RESEARCH, 2013, 19 (15) : 4149 - 4162
  • [46] Sequencing of treatment in metastatic colorectal cancer: Where to fit the target?
    Temraz, Sally
    Mukherji, Deborah
    Shamseddine, Ali
    [J]. WORLD JOURNAL OF GASTROENTEROLOGY, 2014, 20 (08) : 1993 - 2004
  • [47] Identification of Predictive Markers of Response to the MEK1/2 Inhibitor Selumetinib (AZD6244) in K-ras-Mutated Colorectal Cancer
    Tentler, John J.
    Nallapareddy, Sujatha
    Tan, Aik Choon
    Spreafico, Anna
    Pitts, Todd M.
    Morelli, M. Pia
    Selby, Heather M.
    Kachaeva, Maria I.
    Flanigan, Sara A.
    Kulikowski, Gillian N.
    Leong, Stephen
    Arcaroli, John J.
    Messersmith, Wells A.
    Eckhardt, S. Gail
    [J]. MOLECULAR CANCER THERAPEUTICS, 2010, 9 (12) : 3351 - 3362
  • [48] MEK Inhibition Leads to PI3K/AKT Activation by Relieving a Negative Feedback on ERBB Receptors
    Turke, Alexa B.
    Song, Youngchul
    Costa, Carlotta
    Cook, Rebecca
    Arteaga, Carlos L.
    Asara, John M.
    Engelman, Jeffrey A.
    [J]. CANCER RESEARCH, 2012, 72 (13) : 3228 - 3237
  • [49] A role for K-ras in conferring resistance to the MEK inhibitor, CI-1040
    Wang, YL
    Van Becelaere, K
    Jiang, P
    Przybranowski, S
    Omer, C
    Sebolt-Leopold, J
    [J]. NEOPLASIA, 2005, 7 (04): : 336 - 347
  • [50] PI3K Pathway Activation Mediates Resistance to MEK Inhibitors in KRAS Mutant Cancers
    Wee, Susan
    Jagani, Zainab
    Xiang, Kay Xiaoqin
    Loo, Alice
    Dorsch, Marion
    Yao, Yung-Mae
    Sellers, William R.
    Lengauer, Christoph
    Stegmeier, Frank
    [J]. CANCER RESEARCH, 2009, 69 (10) : 4286 - 4293