Key result
GPCR mutations emerge as both cancer drivers and passengers given motif conservation and functional redundancy.
Why the study?
Abnormal expression and mutations of GPCRs have been implicated in cancer, but whether mutations in GPCRs act as cancer drivers or passengers remains an open question.
The review highlights the complex role of GPCR mutations in cancer, suggesting they may act as either drivers or passengers depending on context, and emphasizes the need for multiomics approaches in future drug discovery.
May warrant caution in GPCR-targeted cancer therapies; leaves open context-specific driver status for multiomics studies.
G protein‐coupled receptors (GPCRs) play a crucial role in cellular signalling, regulating various physiological processes. Abnormal expression and mutations of GPCRs have been implicated in several types of cancer, influencing tumour initiation, progression and immune response. In this review, we present an overview of recent research on GPCR involvement in cancer and discuss the evidence supporting whether mutations in GPCRs act as cancer driver or passenger. Accumulation of GPCR mutations in some highly conserved structural motifs and the mutually exclusiveness observed between G i ‐coupled GPCRs and G protein subunit alpha S (GNAS)‐activating mutations indicate their potential driving role in cancer. However, the functional redundancy of GPCR signalling networks together with the widespread but low frequency distribution of GPCR mutations indicate that they may rather act as passengers. The future of GPCR drug discovery hinges on overcoming challenges related to data availability and the integration of GPCR research with broader cancer studies using multiomics approaches.
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Feng et al. (2025) conducted a review in Cancer. GPCR mutations was evaluated on Role of GPCR mutations in cancer (driver vs passenger). GPCR mutations show evidence of being both cancer drivers, due to accumulation in conserved motifs, and passengers, given their functional redundancy and low frequency distribution.
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