TY - JOUR
T1 - Disruptin, a cell-penetrating peptide degrader of EGFR
T2 - Cell-Penetrating Peptide in Cancer Therapy
AU - Mehta, Ranjit K.
AU - Shukla, Sushmita
AU - Ramanand, Susmita G.
AU - Somnay, Vishal
AU - Bridges, Alexander J.
AU - Lawrence, Theodore S.
AU - Nyati, Mukesh K.
N1 - Funding Information:
This work was supported by the National Institutes of Health [ R01 CA131290 to M.K.N.] and the Rogel Cancer Center support grant, P30CA46592. This project is a component of the Protein Folding Disease Research Initiative of the University of Michigan Medical School .
Funding Information:
This work was supported by the National Institutes of Health [R01 CA131290 to M.K.N.] and the Rogel Cancer Center support grant, P30CA46592. This project is a component of the Protein Folding Disease Research Initiative of the University of Michigan Medical School.
Publisher Copyright:
© 2021
PY - 2021/8
Y1 - 2021/8
N2 - Disruptin is a cell-permeable decoy peptide designed to destabilize activated EGFR, both by inhibiting Hsp90 chaperoning and dissociating the active asymmetric EGFR dimer, which leads to an increase in engagement of activated EGFR with the proteolytic degradation machinery and subsequent loss from the cells. Disruptin is an N-terminally biotinylated nonadecapeptide, with 8 amino acids from the αC-helix-β4 sheet loop of EGFR (S767-C774) fused to a TAT undecapeptide. The S767-R775 loop is at the interface with juxtamembrane domains in the active EGFR dimers and is a binding site for Hsp90. Cellular studies in EGFR-activated tumor cells demonstrated that Disruptin causes the disappearance of EGFR protein from cells over a few hours, a growth inhibitory effect, similar but more effective than the EGFR kinase inhibition. Interestingly, cells without activated EGFR remained unaffected. In vivo studies showed that Disruptin slowed the growth of small tumors. Larger tumors responded to intratumoral injections but did not respond to systemic administration at tolerated doses. Investigation of these results revealed that systemic administration of Disruptin has acute toxicities, mainly related to its TAT peptide moiety. Therefore, we conclude that although the efficacy of both in vitro and in vivo intratumoral injection of Disruptin supports the therapeutic strategy of blocking activated EGFR dimerization, Disruptin is not suitable for further development. These studies also highlight the importance of the chosen models and drug-delivery methods for such investigations.
AB - Disruptin is a cell-permeable decoy peptide designed to destabilize activated EGFR, both by inhibiting Hsp90 chaperoning and dissociating the active asymmetric EGFR dimer, which leads to an increase in engagement of activated EGFR with the proteolytic degradation machinery and subsequent loss from the cells. Disruptin is an N-terminally biotinylated nonadecapeptide, with 8 amino acids from the αC-helix-β4 sheet loop of EGFR (S767-C774) fused to a TAT undecapeptide. The S767-R775 loop is at the interface with juxtamembrane domains in the active EGFR dimers and is a binding site for Hsp90. Cellular studies in EGFR-activated tumor cells demonstrated that Disruptin causes the disappearance of EGFR protein from cells over a few hours, a growth inhibitory effect, similar but more effective than the EGFR kinase inhibition. Interestingly, cells without activated EGFR remained unaffected. In vivo studies showed that Disruptin slowed the growth of small tumors. Larger tumors responded to intratumoral injections but did not respond to systemic administration at tolerated doses. Investigation of these results revealed that systemic administration of Disruptin has acute toxicities, mainly related to its TAT peptide moiety. Therefore, we conclude that although the efficacy of both in vitro and in vivo intratumoral injection of Disruptin supports the therapeutic strategy of blocking activated EGFR dimerization, Disruptin is not suitable for further development. These studies also highlight the importance of the chosen models and drug-delivery methods for such investigations.
KW - Cell-Penetrating Peptide
KW - EGFR
KW - HNSCC
KW - Lung Cancer
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U2 - 10.1016/j.tranon.2021.101140
DO - 10.1016/j.tranon.2021.101140
M3 - Article
C2 - 34107419
AN - SCOPUS:85107285368
SN - 1936-5233
VL - 14
JO - Translational Oncology
JF - Translational Oncology
IS - 8
M1 - 101140
ER -