The genetic architecture of bone metastases: unveiling the role of epigenetic and genetic modifications in drug resistance

Abstract

Bone metastases represent frequent and severe complications in various cancers, notably impacting prognosis and quality of life. This review article delves into the genetic and epigenetic mechanisms underpinning drug resistance in bone metastases, a key challenge in effective cancer treatment. The development of drug resistance in cancer can manifest as either intrinsic or acquired, with genetic heterogeneity playing a pivotal role. Intrinsic resistance is often due to pre-existing mutations, while acquired resistance evolves through genetic and epigenetic alterations during treatment. These alterations include mutations in driver genes like TP53 and RB1, epigenetic modifications such as DNA methylation and histone changes, and pathway alterations, notably involving RANK-RANKL signaling and the PI3K/AKT/mTOR cascade. Recent studies underline the significance of the tumor microenvironment in fostering drug resistance, with components such as cancer-associated fibroblasts and hypoxia playing crucial roles. The interactions between metastatic cancer cells and the bone microenvironment facilitate survival and the proliferation of drug-resistant clones. This review highlights the necessity of understanding these complex interactions to develop targeted therapies that can overcome resistance and improve treatment outcomes. Current therapeutic strategies and future directions are discussed, emphasizing the integration of genomic profiling and targeted interventions in managing bone metastases. The evolving landscape of genetic research, including the application of next-generation sequencing and CRISPR technology, offers promising avenues for novel and more effective therapeutic strategies. This comprehensive exploration aims to provide insights into the molecular intricacies of drug resistance in bone metastases, paving the way for improved clinical management and patient care.

Keywords

Bone metastases / drug resistance / genetic alterations / epigenetic modifications / tumor microenvironment

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