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Protacs in oral cancer: degrading oncogenic drivers for next-generation therapy
Pratibha Prasad1,2, Manal Jamil Al Maslamani3, Khuzin Dinislam4
1Basic Medical and Dental Sciences Department, College of Dentistry, Ajman University, Ajman, United Arab Emirates.
Abstract:
Oral squamous cell carcinoma (OSCC) remains difficult to treat because of its intricate molecular profile, its limited responsiveness to conventional therapeutic approaches, and the challenge of targeting key oncogenic drivers with standard drugs. An emerging approach that addresses these limitations is the use of proteolysis-targeting chimeras (PROTACs), which shifts the focus from traditional inhibition of protein activity to the deliberate degradation of disease-associated proteins. PROTACs can eliminate oncogenic proteins like EGFR, STAT3, c-MYC, and anti-apoptotic regulators by hijacking the ubiquitin-proteasome system, many of which are essential for OSCC pathophysiology and are considered undruggable. This method provides a catalytic, sustained mechanism of action and overcomes the resistance arising from target overexpression, mutation, or signaling redundancy. Recent advances in PROTAC design, consisting of orally bioavailable degraders and tissue-directed delivery systems, highlight their translational capacity in epithelial tumors. PROTACs enable degradation of critical effectors involved in proliferation, immune evasion, and therapy resistance in OSCC. Hence, this review highlights how PROTAC technology addresses the current molecular targeting gaps in OSCC and outlines future directions for translating targeted protein degradation into clinical therapy.
Insights
Proteolysis-targeting chimeras (PROTACs) offer a novel strategy for treating oral squamous cell carcinoma (OSCC) by degrading disease-driving proteins. This approach overcomes limitations of conventional therapies and targets previously undruggable proteins in OSCC.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Oral squamous cell carcinoma (OSCC) presents significant treatment challenges due to complex molecular characteristics and resistance to conventional therapies.
- Targeting key oncogenic drivers in OSCC is difficult with standard drugs, necessitating innovative therapeutic strategies.
- Proteolysis-targeting chimeras (PROTACs) represent an emerging therapeutic modality that degrades disease-associated proteins rather than inhibiting their activity.
Purpose of the Study:
- To review the potential of PROTAC technology in addressing molecular targeting gaps in oral squamous cell carcinoma (OSCC).
- To highlight how PROTACs can degrade essential oncogenic proteins implicated in OSCC pathophysiology.
- To outline future directions for translating targeted protein degradation into clinical applications for OSCC.
Main Methods:
- Review of recent advances in PROTAC design and their application in epithelial tumors.
- Discussion of PROTACs' mechanism of action involving the ubiquitin-proteasome system for targeted protein degradation.
- Analysis of PROTACs' capacity to overcome resistance mechanisms in OSCC, such as target overexpression and mutations.
Main Results:
- PROTACs can effectively degrade crucial oncogenic proteins (e.g., EGFR, STAT3, c-MYC) and anti-apoptotic regulators vital for OSCC.
- This targeted protein degradation approach offers a catalytic and sustained mechanism of action.
- PROTACs demonstrate translational capacity in epithelial tumors, with recent advances in oral bioavailability and tissue-directed delivery.
Conclusions:
- PROTAC technology provides a promising solution for targeting previously undruggable proteins in OSCC.
- PROTACs can degrade critical effectors involved in OSCC proliferation, immune evasion, and therapy resistance.
- Further development and clinical translation of PROTACs hold significant potential for improving OSCC treatment outcomes.
