Personalization of prostate cancer therapy through phosphoproteomics

Castration-resistant prostate cancer (CRPC) remains incurable despite the approval of several new treatments. Identification of new biomarkers and therapeutic targets to enable personalization of CRPC therapy, with the aim of maximizing therapeutic responses and minimizing toxicity in patients, is urgently needed. Prostate cancer progression and therapeutic resistance are frequently driven by aberrantly activated kinase signalling pathways that are amenable to pharmacological inhibition. Personalized phosphoproteomics, which enables the analysis of signalling networks in individual tumours, is a promising approach to advance personalized therapy by discovering biomarkers of pathway activity and clinically actionable targets. Several technologies for global and targeted phosphoproteomic analysis exist, each with its own strengths and shortcomings. Global discovery phosphoproteomics is predominantly conducted using liquid chromatography–tandem mass spectrometry coupled with data-dependent or data-independent acquisition technologies. Multiplexed targeted phosphoproteomics can be divided into platforms based on mass spectrometry or antibodies, including selected or parallel reaction monitoring and triggered by offset, multiplexed, accurate mass, high-resolution, absolute quantification (known as TOMAHAQ) or forward-phase or reverse-phase protein arrays, respectively. Several obstacles still need to be overcome before the full potential of phosphoproteomics can be realized in routine clinical practice, but a future phosphoproteomics-centric trans-omic profiling approach should enable optimized personalized CRPC management through improved biomarkers and targeted treatments. Yang and colleagues discuss the clinical need and rationale for a phosphoproteomics approach to personalizing prostate cancer treatment. They describe current technologies, clinical findings, and challenges and strategies to realizing routine clinical application of phosphoproteomics. Key points To improve outcomes of patients with castration-resistant prostate cancer, identification of new biomarkers and therapeutic targets is needed to enable personalized management with maximized therapeutic responses and minimized toxicity. Aberrantly activated kinase signalling frequently drives prostate cancer progression and therapeutic resistance but might be amenable to pharmacological inhibition. Phosphoproteomics approaches that enable the analysis of signalling networks in individual tumours are