Open AccessEGFR targeting monoclonal antibody combines with an mTOR inhibitor and potentiates tumor inhibition by acting on complementary signaling hubs
Author(s) -
James Roshan,
Vishwakarma Siddharth,
Chivukula Indira V.,
Basavaraj Chetana,
Melarkode Ramakrishnan,
Montero Enrique,
Nair Pradip
Publication year - 2012
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.21
Subject(s) - in vivo , monoclonal antibody , pi3k/akt/mtor pathway , signal transduction , epidermal growth factor receptor , cancer research , in vitro , pharmacology , antibody , growth inhibition , severe combined immunodeficiency , biology , receptor , chemistry , medicine , immunology , microbiology and biotechnology , biochemistry
N imotuzumab, an anti‐epidermal growth factor receptor (anti‐ EGFR ) monoclonal antibody, has been used extensively in many solid tumors and confers significant survival advantage. The antibody has limited skin toxicity and is generally well tolerated. Similar to other anti‐ EGFR therapies, patients may relapse a few months after treatment. In this study we show for the first time, the use of N imotuzumab along with S irolimus has synergistic effect on tumor inhibition as compared with the drugs used individually, in N imotuzumab responsive and nonresponsive cell lines. In vitro studies prove that while S irolimus (25 nmol/L) affects the signal downstream to mammalian target of rapamycin (mTOR) , N imotuzumab (83 nmol/L) downregulates pTYR , pMAPK and pSTAT 3 by 40%, 20% and 30%, respectively. The combination, targeting these two different signaling hubs, may be associated with the synergistic inhibition observed. In vivo, the use of half human therapeutic equivalent doses for both the drugs substantially reduces tumors established in nude as well as severe combined immunodeficiency (SCID) mice by EGFR overexpressing A‐431 cells. The drug combination reduces cell proliferation and the expression of signal transduction molecules. Treated tumors are better differentiated as compared with those established in the control mice. Tumor microarray demonstrates that N imotuzumab and the combination groups segregate independently to the S irolimus and the control treatment. The combination uniquely downregulated 55% of the altered tumor genes, extending beyond the typical pathways associated with N imotuzumab and S irolimus downstream pathways inhibition. These results would suggest that this nontoxic drug combination improves therapeutic benefit even in patients with low‐ EGFR expression and severely immunocompromised because of their current medication.