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The great escape: tumour cell plasticity in resistance to targeted therapy
Soufiane Boumahdi1, Frederic J de Sauvage2
1Department of Molecular Oncology, Genentech, South San Francisco, CA, USA.
Abstract:
The success of targeted therapies in cancer treatment has been impeded by various mechanisms of resistance. Besides the acquisition of resistance-conferring genetic mutations, reversible mechanisms that lead to drug tolerance have emerged. Plasticity in tumour cells drives their transformation towards a phenotypic state that no longer depends on the drug-targeted pathway. These drug-refractory cells constitute a pool of slow-cycling cells that can either regain drug sensitivity upon treatment discontinuation or acquire permanent resistance to therapy and drive relapse. In the past few years, cell plasticity has emerged as a mode of targeted therapy evasion in various cancers, ranging from prostate and lung adenocarcinoma to melanoma and basal cell carcinoma. Our understanding of the mechanisms that control this phenotypic switch has also expanded, revealing the crucial role of reprogramming factors and chromatin remodelling. Further deciphering the molecular basis of tumour cell plasticity has the potential to contribute to new therapeutic strategies which, combined with existing anticancer treatments, could lead to deeper and longer-lasting clinical responses.
Insights
Tumor cells can evade targeted cancer therapies through reversible drug tolerance, a process called cell plasticity. Understanding this mechanism is key to developing new treatments that prevent cancer relapse.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Targeted cancer therapies face challenges due to resistance mechanisms.
- Beyond genetic mutations, reversible drug tolerance allows cancer cells to survive therapy.
- Tumor cell plasticity enables a phenotypic switch, leading to drug-refractory states.
Purpose of the Study:
- To explore the role of cell plasticity in targeted therapy evasion.
- To understand the mechanisms underlying phenotypic switching in cancer cells.
- To identify potential therapeutic strategies targeting cell plasticity.
Main Methods:
- Review of current literature on cancer cell plasticity and resistance.
- Analysis of studies investigating phenotypic switching in various cancer types.
- Examination of the role of reprogramming factors and chromatin remodeling.
Main Results:
- Cell plasticity is a significant mechanism for evading targeted therapies across multiple cancer types.
- This phenotypic plasticity involves slow-cycling, drug-refractory cells.
- Reprogramming factors and chromatin remodeling are critical in controlling this switch.
Conclusions:
- Cell plasticity is a crucial factor in targeted therapy resistance and cancer relapse.
- Deciphering the molecular basis of plasticity can lead to novel therapeutic approaches.
- Targeting cell plasticity may enhance the efficacy of existing cancer treatments for durable responses.
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