EGFR targeting monoclonal antibody combines with an mTOR inhibitor and potentiates tumor inhibition by acting on complementary signaling hubs.
Nimotuzumab, 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 Nimotuzumab along with Sirolimus has synergistic effect on tumor inhibition as compared with the drugs used individually, in Nimotuzumab responsive and nonresponsive cell lines. In vitro studies prove that while Sirolimus (25 nmol/L) affects the signal downstream to mammalian target of rapamycin (mTOR), Nimotuzumab (83 nmol/L) downregulates pTYR, pMAPK and pSTAT3 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 Nimotuzumab and the combination groups segregate independently to the Sirolimus and the control treatment. The combination uniquely downregulated 55% of the altered tumor genes, extending beyond the typical pathways associated with Nimotuzumab and Sirolimus 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.
Biocon Ltd., R&D, Drug Development Group Bangalore, 560100, India.
Roshan
R
James
Siddharth
S
Vishwakarma
Indira V
IV
Chivukula
Chetana
C
Basavaraj
Ramakrishnan
R
Melarkode
Enrique
E
Montero
Pradip
P
Nair
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols; D049109:Cell Proliferation; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D058990:Molecular Targeted Therapy; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D061067:Antibodies, Monoclonal, Humanized; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C501466:nimotuzumab; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D020123:Sirolimus
Immunotherapy; Nimotuzumab; Sirolimus; signal transduction; synergy