Disruptin, a cell-penetrating peptide degrader of EGFR

• Published in: Translational oncology 2021-08, Vol.14 (8), p.101140, Article 101140
• Main Authors: Mehta, Ranjit K., Shukla, Sushmita, Ramanand, Susmita G., Somnay, Vishal, Bridges, Alexander J., Lawrence, Theodore S., Nyati, Mukesh K.
• Format: Article
• Language: English
• Subjects: Cell-Penetrating Peptide; EGFR; HNSCC; Lung Cancer
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2021.101140

•Systemic injection of Disruptin is effective in small tumors but was minimally effective in animals with established tumors.Intratumoral injections of Disruptin reduced EGFR protein level and slowed tumor growth.•Disruptin peptide causes the disappearance of EGFR protein and also affect angiogenesis.•The Disruptin peptide was toxic when dosed systemically.•Overall, these findings suggest that an agent that can reduce EGFR protein could offer an alternate therapy for EGFR driven tumors. 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.