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Updated: Sep 18, 2025
A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
The rise of new targets in melanoma
1Department of Medicine, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
Abstract:
Despite advancements in cancer treatment, the clinical options remain limited and therapeutic resistance inevitably develops. In melanoma, the second most commonly mutated driver oncogene is NRAS, which remains undruggable by small molecular agents. For those treated with BRAF/MEK combination therapy, in the setting of BRAF V600 mutations, or immunotherapies regardless of somatic genetic makeup, resistance eventually develops in the majority of cases. Developing rational combination therapies, as suggested by preclinical studies involving genetic manipulation of resistance mediators, necessitates a substantial expansion of druggable targets. Novel chemistry strategies, such as chemoproteomics platforms and chemical inducer of proximity (CIP) agents, offer promising solutions. Chemoproteomics enables the rapid identification of ligands to guide medicinal chemistry, while CIP agents alter the expression levels of key proteins. Using proteins encoded by oncogenes (such as NRAS) and p53 as pivotal resistance mediators, and the lineage-specific transcription factor SRY-box transcription factor 10 (SOX10) in melanoma as illustrative examples, we demonstrate how these technologies can be leveraged to rapidly expand the druggable target pool and overcome resistance mechanisms, ultimately paving the way for regimens that produce deeper and more durable responses.
Insights
Novel chemistry strategies like chemoproteomics and chemical inducers of proximity (CIP) can expand druggable targets. These approaches aim to overcome therapeutic resistance in cancers like melanoma, leading to more durable responses.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Cancer therapies face limitations due to therapeutic resistance, particularly in melanoma.
- Neuroblastoma rat sarcoma viral oncogene homolog (NRAS) is a key undruggable oncogene in melanoma, and resistance develops to BRAF/MEK and immunotherapy.
- Expanding druggable targets is crucial for developing effective combination therapies against cancer resistance.
Purpose of the Study:
- To demonstrate how novel chemistry strategies can expand the pool of druggable targets.
- To illustrate the application of chemoproteomics and chemical inducer of proximity (CIP) agents in overcoming resistance mechanisms.
- To explore the use of NRAS, p53, and SOX10 as examples for targeting resistance in melanoma.
Main Methods:
- Utilizing chemoproteomics platforms for rapid identification of potential drug ligands.
- Employing chemical inducer of proximity (CIP) agents to modulate key protein expression levels.
- Investigating oncogenes (NRAS), tumor suppressors (p53), and transcription factors (SOX10) as mediators of resistance.
Main Results:
- Chemoproteomics enables swift ligand discovery for medicinal chemistry efforts.
- CIP agents offer a mechanism to alter the expression of critical resistance-mediating proteins.
- These technologies show potential in identifying and targeting key players in melanoma resistance.
Conclusions:
- Novel chemistry strategies, including chemoproteomics and CIP, can significantly expand druggable targets.
- These approaches are vital for overcoming therapeutic resistance in cancers like melanoma.
- Leveraging these technologies can lead to the development of combination therapies for deeper and more durable patient responses.
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