Plasticity in Cancer Cells: The Master Engine of Therapeutic Resistance and Tumor Evolution

Cancer cell plasticity refers to the ability of cancer cells to change their phenotype and is one of the primary requirements for metastasis. It is considered one of the main contributors to intratumoral heterogeneity, a key factor in the development of cancer, and is known to alter responses and resistance to different forms of therapy. However, tumour cells are impaired in various cellular signalling pathways, such as mitogen-activated protein kinases, phosphoinositide-3-kinases, Wnt, Hedgehog, and Notch, as well as in epithelial-mesenchymal transition (EMT) and phenotypic plasticity. Cancer stem cells (CSCs) are considered an integral part of tumour plasticity, as they have the capacity to proliferate, differentiate, and initiate the growth of tumours. Recent studies suggest that targeting signals from the tumor microenvironment, plasticity-related pathways, and epigenetic regulators may offer promising therapeutic options to improve long-term response and reduce phenotypic dysregulation. This approach, which emphasizes plasticity as a primary biological driving force rather than a secondary one, allows cancer cells to change from an epithelial, mesenchymal, stem cell, or dormant state to a drug-resistant state in response to environmental stimuli. Taken together, these results suggest that cellular plasticity is important in tumour development and treatment failure. Therefore, targeting pathways associated with plasticity, modifying the tumour microenvironment, and using adaptive therapies may improve long-term tumour control.