Publication Highlights: Feb 2022

In the Journal of Medicinal Chemistry, Tamas Yelland and Esther Garcia presented a novel, alternative KRAS targeting strategy - tagging it for relocation to the cytoplasm. While sustaining KRAS binding to the protein PDE6D, KRAS moved away from its usual site of action at the cell membrane, leading to reduced downstream KRAS-oncogenic signalling. As the levels of the two proteins naturally vary between cell types, further study is required to develop a KRAS:PDE6D stabiliser that could be used as a successful anti-cancer therapy.

Together with Beatson scientists, Tim Humpton (from the Vousden lab at the Francis Crick Institute) has described an easier way of tracking p53 activity. The study, published in Science Signaling, introduced a new near-infrared reporter that enables investigation of p53's role in health and disease without the need for further intervention. While confirming the role of p53 in the liver after irradiation or paracetamol treatment, further applications of the reporter will allow the study of p53 activity during tumour development, offering insights into when to attempt therapeutic intervention.

Dominik Koessinger, David Novo and colleagues made a pre-print available on bioRxiv that identified a cell communication tool involving p53-mutant glioblastoma cells releasing extracellular vesicles. Favouring the sorting of podocalyxin into these vesicles stimulated other brain cells to create an invasive environment and promoted cancer cell infiltration in the brain. This study highlighted potential druggable targets for a form of glioblastoma with a particularly poor prognosis.

In a collaborative effort led by Beatson scientists and the University of Newcastle, a pre-print on bioRxiv showed that inhibiting CXCR2 could sensitise liver cancer to immunotherapy when patients were also affected by non-alcoholic fatty liver disease. Mechanistically, the treatment switched tumour neutrophils to an anti-tumour phenotype and enhanced the response of other immune cells. This suggests anti-CXCR2 therapy might be a promising anti-cancer agent in patients with liver cancer.

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