Cancer drug resistance as learning of signaling networks
Dávid Keresztes1, Márk Kerestély1, Levente Szarka1
1Department of Molecular Biology, Semmelweis University, Budapest, Hungary.
Abstract:
Drug resistance is a major cause of tumor mortality. Signaling networks became useful tools for driving pharmacological interventions against cancer drug resistance. Signaling datasets now cover the entire human cell. Recently, network adaptation became understood as a learning process. We review rapidly increasing evidence showing that the development of cancer drug resistance can be described as learning of signaling networks. During drug adaptation, the network forgets drug-affected pathways by desensitization and relearns by strengthening alternative pathways. Thus, resistant cancer cells develop a drug resistance memory. We show that all key players of cellular learning (i.e., IDPs, protein translocation, microRNAs/lncRNAs, scaffolding proteins and epigenetic/chromatin memory) have important roles in the development of cancer drug resistance. Moreover, all of them are central components of the epithelial-mesenchymal transition leading to metastases and resistance. Phenotypic plasticity was recently listed as a hallmark of cancer. We review how network plasticity induces rare, pre-existent drug-resistant cells in the absence of drug treatment. Key network methods assessing the development of drug resistance and network pharmacological interventions against drug resistance are summarized. Finally, we highlight the class of cellular memory drugs affecting cellular learning and forgetting, and we summarize current challenges to prevent or break drug resistance using network models.
Insights
Cancer drug resistance develops through a cellular learning process where signaling networks adapt and form a "drug resistance memory." This involves forgetting old pathways and strengthening new ones, impacting treatment outcomes.
Area of Science:
- Oncology
- Systems Biology
- Pharmacology
Background:
- Drug resistance significantly contributes to cancer mortality.
- Signaling networks are crucial for understanding and intervening in cancer drug resistance.
- Recent research views network adaptation as a learning process.
Purpose of the Study:
- To review evidence linking cancer drug resistance to signaling network learning.
- To explore the role of cellular learning mechanisms in drug resistance.
- To summarize network-based interventions and challenges in overcoming drug resistance.
Main Methods:
- Review of current scientific literature on cancer signaling networks and drug resistance.
- Analysis of cellular learning processes (e.g., desensitization, pathway strengthening).
- Examination of key molecular players in cellular learning and their role in drug resistance and metastasis.
Main Results:
- Cancer drug resistance can be conceptualized as a learning process in signaling networks, forming a 'drug resistance memory'.
- Cellular learning components like intrinsically disordered proteins (IDPs), microRNAs, and epigenetic modifications are vital for drug resistance.
- Network plasticity drives the emergence of pre-existent drug-resistant cells, contributing to cancer hallmarks like epithelial-mesenchymal transition.
Conclusions:
- Signaling network adaptation and cellular learning are central to the development of cancer drug resistance.
- Understanding these learning mechanisms opens avenues for novel therapeutic strategies, including 'cellular memory drugs'.
- Addressing challenges in network modeling is critical for preventing and overcoming drug resistance.
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