Efficacy of an EGFR-specific peptide against EGFR-dependent cancer cell lines and tumor xenografts.
We have recently synthesized a peptide called Disruptin, which comprised the SVDNPHVC segment of the epidermal growth factor receptor (EGFR) that inhibits binding of heat shock protein 90 (Hsp90) to the EGFR and EGF-dependent EGFR dimerization to cause EGFR degradation. The effect is specific for EGFR versus other Hsp90 client proteins [Ahsan et al.: (2013). Destabilization of the epidermal growth factor receptor (EGFR) by a peptide that inhibits EGFR binding to heat shock protein 90 and receptor dimerization. J Biol Chem288, 26879-26886]. Here, we show that Disruptin decreases the clonogenicity of a variety of EGFR-dependent cancer cells in culture but not of EGFR-independent cancer or noncancerous cells. The selectivity of Disruptin toward EGFR-driven cancer cells is due to the high level of EGF stimulation of EGFR in EGFR-dependent tumor cells relative to normal cells. When administered by intraperitoneal injection into nude mice bearing EGFR-driven human tumor xenografts, Disruptin causes extensive degradation of EGFR in the tumor but not in adjacent host tissue. Disruptin markedly inhibits the growth of EGFR-driven tumors without producing the major toxicities caused by the Hsp90 inhibitor geldanamycin or by cisplatin. These findings provide proof of concept for development of a new Disruptin-like class of antitumor drugs that are directed specifically against EGFR-driven tumors.
Department of Radiation Oncology, The University of Michigan Medical School, Ann Arbor, MI.
Aarif
A
Ahsan
Department of Radiation Oncology, The University of Michigan Medical School, Ann Arbor, MI.
Susmita G
SG
Ramanand
Unit for Laboratory Animal Medicine, The University of Michigan Medical School, Ann Arbor, MI.
Ingrid L
IL
Bergin
Department of Biostatistics, The University of Michigan Medical School, Ann Arbor, MI.
Lilli
L
Zhao
Department of Radiology, The University of Michigan Medical School, Ann Arbor, MI.
Christopher E
CE
Whitehead
Department of Radiation Oncology, The University of Michigan Medical School, Ann Arbor, MI.
Alnawaz
A
Rehemtulla
Department of Radiation Oncology, The University of Michigan Medical School, Ann Arbor, MI.
Dipankar
D
Ray
Department of Pharmacology, The University of Michigan Medical School, Ann Arbor, MI.
William B
WB
Pratt
Department of Radiation Oncology, The University of Michigan Medical School, Ann Arbor, MI.
Theodore S
TS
Lawrence
Department of Radiation Oncology, The University of Michigan Medical School, Ann Arbor, MI. Electronic address: nyati@umich.edu.
Mukesh K
MK
Nyati
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D016466:CHO Cells; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003412:Cricetulus; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D059748:Proteolysis; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D010446:Peptide Fragments; C584969:epidermal growth factor receptor (768-775); C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin