Cancer cell metastasis and drug resistance: Unravelling the role of NF-κB and cyclin D1 pathways and their crosstalk.

The emergence of drug resistance in cancer therapy remains a formidable challenge. NF-κB transcription factor is considered a central player in therapeutic resistance and tumor relapse. Upon activation, NF-κB dimers trigger a cascade of downstream signaling and transcriptional events that promote cell proliferation and survival. One of the key NF-κB targets is cyclin D1, which facilitates uncontrolled cell division in both CDK-dependent and independent manners. NF-κB-mediated upregulation of cyclin D1 is associated with drug resistance by activating multiple mechanisms, including anti-apoptotic pathways, epithelial-to-mesenchymal transition, epigenetic modifications, and DNA damage repair. Therefore, a comprehensive understanding of the interplay between NF-κB and cyclin D1 may inform the development of improved therapeutic strategies that simultaneously target multiple resistance pathways and suppress the growth, proliferation, and metastasis of cancer cells. This review focuses on the molecular mechanisms by which the NF-κB and cyclin D1 axis contributes to drug resistance, explores its crosstalk with other oncogenic pathways, and discusses the pivotal roles as a therapeutic target and clinical trials with an agent that targets the NF-κB signaling pathway. By unravelling the intricate dynamics of this axis, we can pave the way for more effective strategies to overcome drug resistance in cancer therapy.