TITLE

Oncogenic RAS simultaneously protects against anti-EGFR antibody-dependent cellular cytotoxicity and EGFR signaling blockade

AUTHOR(S)
Kasper, S; Breitenbuecher, F; Reis, H; Brandau, S; Worm, K; Köhler, J; Paul, A; Trarbach, T; Schmid, K W; Schuler, M
PUB. DATE
June 2013
SOURCE
Oncogene;6/6/2013, Vol. 32 Issue 23, p2873
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Monoclonal antibodies against the epidermal growth factor receptor (EGFR) are effective cancer therapeutics, but tumors harboring RAS mutations are resistant. To functionally dissect RAS-mediated resistance, we have studied clinically approved anti-EGFR antibodies, cetuximab and panitumumab, in cancer models. Both antibodies were equally cytotoxic in vitro. However, cetuximab, which also triggers antibody-dependent cellular cytotoxicity (ADCC), was more effective than panitumumab in vivo. Oncogenic RAS neutralized the activity of both antibodies in vivo. Mechanistically, RAS upregulated BCL-XL in cancer cell lines and in primary colorectal cancers. Suppression of BCL-XL by short hairpin RNA or treatment with a BH3 mimetic overcame RAS-mediated antibody resistance. In conclusion, RAS-mutant tumors escape anti-EGFR antibody-mediated receptor blockade as well as ADCC in vivo. Pharmacological targeting of RAS effectors can restore sensitivity to antibody therapy.
ACCESSION #
87970113

 

Related Articles

  • Hyperactivation of EGFR and downstream effector phospholipase D1 by oncogenic FAM83B. Cipriano, R.; Bryson, B. L.; Miskimen, K. L. S.; Bartel, C. A.; Hernandez-Sanchez, W.; Bruntz, R. C.; Scott, S. A.; Lindsley, C. W.; Brown, H. A.; Jackson, M. W. // Oncogene;6/19/2014, Vol. 33 Issue 25, p3298 

    Despite the progress made in targeted anticancer therapies in recent years, challenges remain. The identification of new potential targets will ensure that the arsenal of cancer therapies continues to expand. FAM83B was recently discovered in a forward genetic screen for novel oncogenes that...

  • Hyperactivation of constitutively dimerized oncogenic EGF receptors by autocrine loops. Laisney, J A G C; Mueller, T D; Schartl, M; Meierjohann, S // Oncogene;5/9/2013, Vol. 32 Issue 19, p2403 

    The epidermal growth factor (EGF) receptor (EGFR) has a key role in normal embryonic development, adult tissue homeostasis and many pathological processes, in particular tumour formation. Aberrant EGFR activation occurs in many cancer types, and inhibition of this receptor is a promising...

  • A comparative survey of functional footprints of EGFR pathway mutations in human cancers. Lane, A; Segura-Cabrera, A; Komurov, K // Oncogene;10/23/2014, Vol. 33 Issue 43, p5078 

    Genes functioning in epidermal growth factor receptor (EGFR) signaling pathways are among the most frequently activated oncogenes in human cancers. We have conducted a comparative analysis of functional footprints (that is, effect on signaling and transcriptional landscapes in cells) associated...

  • Targeting molecular addictions in cancer. Vivanco, I // British Journal of Cancer;11/25/2014, Vol. 111 Issue 11, p2033 

    Cancer cells depend on a finite number of critical signals for their survival. Oncogene addiction, that is, the acquired dependence of a cancer cell on the activity of a single oncogenic gene product, has been the basis for the targeted therapy paradigm, and operationally defines such signals....

  • Oncogenic K-Ras and Loss of Smad4 Mediate Invasion by Activating an EGFR/NF-κB Axis That Induces Expression of MMP9 and uPA in Human Pancreas Progenitor Cells. Bera, Alakesh; Zhao, Shujie; Cao, Lin; Chiao, Paul J.; Freeman, James W. // PLoS ONE;Dec2013, Vol. 8 Issue 12, p1 

    Activating K-Ras mutations and inactivating mutations of Smad4 are two common genetic alterations that occur in the development and progression of pancreatic ductal adenocarcinomas (PDAC). To further study the individual and combinatorial roles of these two mutations in the pathogenesis of PDAC,...

  • MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches. Kufe, D W // Oncogene;2/28/2013, Vol. 32 Issue 9, p1073 

    Mucin 1 (MUC1) is a heterodimeric protein formed by two subunits that is aberrantly overexpressed in human breast cancer and other cancers. Historically, much of the early work on MUC1 focused on the shed mucin subunit. However, more recent studies have been directed at the transmembrane...

  • In vitro and in vivo anti-tumor activities of anti-EGFR single-chain variable fragment fused with recombinant gelonin toxin. Zhou, Xikun; Qiu, Ji; Wang, Zhen; Huang, Nongyu; Li, Xiaolei; Li, Qian; Zhang, Yinbing; Zhao, Chengjian; Luo, Can; Zhang, Nannan; Teng, Xiu; Chen, Zhongwen; Liu, Xiao; Yu, Xianlian; Wu, Wenling; Wei, Yu-quan; Li, Jiong // Journal of Cancer Research & Clinical Oncology;Jul2012, Vol. 138 Issue 7, p1081 

    Purpose: Epidermal growth factor receptor (EGFR) plays an important role in the growth and metastasis of many solid tumors. Strategies that target EGFR hold promising therapeutic potential for the treatment for non-small cell lung cancer (NSCLC), as EGFR is normally overexpressed in these...

  • TLR3 agonists improve the immunostimulatory potential of cetuximab against EGFR+ head and neck cancer cells. Chwee Ming Lim; Stephenson, Ryan; Salazar, Andres M.; Ferris, Robert L. // OncoImmunology;Jun2013, Vol. 2 Issue 6, pe24677-1 

    Toll-like receptor 3 (TLR3) agonists have been extensively used as adjuvants for anticancer vaccines. However, their immunostimulatory effects and precise mechanisms of action in the presence of antineoplastic monoclonal antibodies (mAbs) have not yet been evaluated. We investigated the effect...

  • Adipose cells promote resistance of breast cancer cells to trastuzumab-mediated antibody-dependent cellular cytotoxicity. Minh Ngoc Duong; Cleret, Aurore; Matera, Eva-Laure; Chettab, Kamel; Mathé, Doriane; Valsesia-Wittmann, Sandrine; Clémenceau, Béatrice; Dumontet, Charles // Breast Cancer Research;2015, Vol. 17 Issue 1, p1 

    Introduction: Trastuzumab has been used in the treatment of human epidermal growth factor receptor 2 (HER2)-expressing breast cancer, but its efficacy is limited by de novo or acquired resistance. Although many mechanisms have been proposed to explain resistance to trastuzumab, little is known...

Share

Read the Article

Courtesy of VIRGINIA BEACH PUBLIC LIBRARY AND SYSTEM

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics