THE INTEGRATED stress response (ISR) plays a vital role in helping tumour cells adapt to their environment, ensuring survival and promoting progression. Recent research sheds light on a promising therapeutic strategy for tackling prostate cancer (PCa) by targeting the ISR kinase GCN2, especially in tumours lacking the transcription factor p53.
GCN2, a key component of the ISR, is responsible for maintaining amino acid balance in tumour cells, which is crucial for their growth. However, its inhibition creates a cascade of nutrient deficiencies, notably in purine nucleotides essential for DNA synthesis. This deficiency triggers a checkpoint mechanism that relies on p53 signalling to induce cell cycle arrest and senescence, effectively halting tumour progression.
In p53-deficient PCa cells, this stress response mechanism is absent, leaving the cells unable to cope with the nucleotide shortfall. Consequently, GCN2 inhibition leads to cell death in these p53-deficient tumours. In contrast, tumours with functional p53 activate protective mechanisms, reducing the impact of GCN2 inhibition.
Experimental studies in mice highlight the potential of this approach as GCN2 inhibition significantly slowed tumour growth in p53-functional cancers but demonstrated even greater efficacy in inducing cell death in p53-deficient tumours. This is particularly noteworthy, as p53 mutations often pose a significant challenge in cancer treatment.
The study also explores the interplay between GCN2 and p53 during nutrient stress. It reveals that GCN2 loss impairs ribosome biogenesis through reduced purine availability, activating a ribosome biogenesis checkpoint. Combining GCN2 inhibition with strategies to further suppress purine biosynthesis amplifies the effects, reducing proliferation and increasing tumour cell death in models ranging from cell lines to organoids and xenografts.
This dual-targeted approach opens exciting avenues for PCa therapy. By exploiting the vulnerabilities of p53-deficient tumours and targeting GCN2, researchers may develop innovative treatments, offering hope for improved outcomes in prostate cancer patients.
Katie Wright, EMJ
Reference
Cordova RA et al. Coordination between the eIF2 kinase GCN2 and p53 signaling supports purine metabolism and the progression of prostate cancer. Sci Signal. 2024;17(864):eadp1375.
