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Glioblastoma is characterised by high levels of intratumoural heterogeneity and plasticity, hindering treatment. Here, the authors develop an analytical framework, scFOCAL, to predict the sensitivity of glioblastoma cell subpopulations to therapies based on reversal of disease transcriptional signatures to identify synergistic therapeutic combinations.

A combination of pyrimidine biosynthesis inhibitors and antiviral nucleoside analogues can boost the antiviral effect of nucleoside analogues against SARS-CoV-2.

RH5, which is part of the trimeric RCR-complex essential for invasion, is a vaccine candidate for malaria. Here, Williams et al. show that monoclonal antibodies targeting each of the three proteins in the RCR-complex can work together to more effectively block the invasion of red blood cells by Plasmodium falciparum and design a combination vaccine candidate.

Antibodies can have synergistic effects, but mechanisms are not well understood. Here, Ragotte et al. identify three antibodies that bind neighbouring epitopes on CyRPA, a malaria vaccine candidate, and show that lateral interactions between the antibodies slow dissociation and inhibit parasite growth synergistically.

This study shows that p300/CBP-dependent H2B acetylation is crucial for maintaining transcription of oncogenic gene programs in androgen receptor-driven prostate cancer.

A highly potent and selective small-molecule catalytic inhibitor of the protein lysine methyltransferase NSD2 shows therapeutic efficacy in preclinical models of KRAS-driven pancreatic cancer and lung cancer.

Quantifying genomic aberrations resulting from designer nucleases activity is essential for gene therapy clinical translation. Here, the authors present a modular digital PCR technique that profiles DNA repair precision and cut-repair cycles at the edited loci, exposing current evaluation biases.

The structure of a neutralizing human monoclonal antibody isolated from an individual immunized in a Plasmodium vivax Duffy binding protein vaccine clinical trial, in complex with its target, elucidates the mechanism by which parasite invasion of immature red blood cells is inhibited.

Using large-scale, systems biology approaches, we can now systematically map synergistic and antagonistic interactions between drugs. Consequently, drug antagonism is providing us with insight into the functions and relatedness of cellular components, mechanisms of drug action and novel ways to inhibit the evolution of antibiotic resistance.

As presented at the ESMO Congress 2025: Results of the phase 2/3 AGITG DYNAMIC-III trial show that de-escalated chemotherapy based on ctDNA-negative status in patients with stage III colon cancer did not meet non-inferiority for 3-year recurrence-free survival when compared to standard of care, although it enables better informed treatment decisions.

The 3CL protease of SARS-CoV-2 is inhibited by PF-00835231 in vitro. Here, the authors show that the prodrug PF-07304814 has broad spectrum activity, inhibiting SARS-CoV and SARS-CoV-2 in mice and its ADME and safety profile support clinical development.

RMC-7977, a multi-selective RAS(ON) inhibitor, exhibits potent tumour-selective activity in multiple pre-clinical models of pancreatic ductal adenocarcinoma through a combination of pharmacology and oncogene dependence.

A potent and selective inhibitor of KRAS^G12D, the most common mutant form of the KRAS oncoprotein, has anti-tumor efficacy in multiple pre-clinical cancer models, opening the possibility to therapeutically target this highly prevalent oncogenic driver.

Analysis of B-cell leukaemia samples reveals that oncogenic mutations do not cause malignant transformation unless they converge on the same signalling pathway, and that it may be possible clinically to combine inhibition of the principal oncogenic driver with reactivation of divergent pathways.

The discovery of a specific CDK12 bivalent degrader, BSJ-4-116, reveals that chronic exposure of MOLT-4 and Jurkat cells to BSJ-4-116 leads to acquired resistance to the compound via point mutations in the CDK12 kinase domain.

Acquired resistance limits the efficacy of PARP inhibitors (PARPi) in high grade serous ovarian cancer (HGSOC). Here, the authors show that inhibition of RNA polymerase I transcription using CX-5461 increases the therapeutic efficacy of PARPi and overcomes PARPi resistance in PDX models of HGSOC.

Multiomic analysis of blast-phase myeloproliferative neoplasms identifies a chromosome 21 amplicon harboring DYRK1A as a clonal and therapeutically targetable event in around a quarter of cases.

The development of selective ubiquitin-specific protease-7 (USP7) inhibitors GNE-6640 and GNE-6776, which induce tumour cell death and reveal differential kinetics of Lys-48 and Lys-63-linked ubiquitin chain depolymerization by USP7.

Hagenbeek et al. identify a small-molecule pan-TEAD inhibitor that blocks the interaction between YAP/TAZ and TEAD proteins. They demonstrate that treatment with the inhibitor leads to antitumor activity and can synergize with KRAS G12C inhibition.

The folate pathway enzyme MTHFD1 is recruited to chromatin by BRD4. Inhibition of BRD4 or MTHFD1 similarly changes nuclear metabolite composition and gene expression, and dual inhibition synergistically impairs cancer cell viability.

Here the authors discover that furanodienone (FDN), a small molecule derived from ginger, exhibits PXR agonist activity selective for the intestine and show that when FDN is administered orally in pharmacological doses ameliorates induced colitis in male mice.

CRISPR screen identifies coactivators of the androgen receptor (AR) complex, including NSD2. NSD2 contributes to AR cistrome reprogramming during prostate cancer progression, and its degradation via a novel PROTAC reduces prostate cancer cell viability in vitro.

Cancer cells rely on selenium uptake and selenocysteine biosynthesis to avoid ferroptosis. However, this mechanism makes them dependent on SEPHS2, an enzyme in the selenocysteine biosynthesis pathway for the detoxification selenide that is produced during selenocysteine formation.

The expression of oncogenic MYC paralogs in small cell lung cancer is mutually exclusive. In this study, the authors show that MYC, but not MYCN or MYCL, represses BCL2, resulting in cells that are uniquely sensitive to apoptosis, and find that CHK1 and AURKA inhibitors may be useful for treating these cancers.

Efficient statistical emulation of melting land ice under various climate scenarios to 2100 indicates a contribution from melting land ice to sea level increase of at least 13 centimetres sea level equivalent.

BET-bromodomain inhibitors could be used to treat medulloblastoma tumors with Myc amplifications. Here, the authors show that both the response and resistance to BET inhibitors in mice is mediated by bHLH/homeobox transcription factors.

Golub and colleagues tested thousands of drugs not originally developed for oncology across 578 human cancer cell lines, revealing growth-inhibitory effects and providing a resource to identify drugs with the potential to be repurposed for cancer.

Just et al. develop a highly accurate biological classification method for identifying suicidal ideators by applying machine learning to neural representations of death- and life-related concepts.

Circulating tumour DNA can provide useful information on disease burden. Here, the authors analysed circulating tumour DNA from 800 patients from a breast cancer clinical trial and investigate the subclonal nature of the disease, and identify DNA mutations associated with resistance and poor survival.

Circulating tumor DNA (ctDNA) may provide a prediction of treatment response, but could be impacted by tumor heterogeneity. Here, the authors investigate ctDNA in CDK4/6 inhibitor treatment in advanced breast cancer, finding ctDNA levels predict progression-free survival and anticipate clonal selection.

The phase 3 TNT Trial in subjects with triple-negative breast cancer supports the superiority of carboplatin over docetaxel in BRCA1/2-mutated tumors and a greater response to taxanes in the nonbasal subtype.

The generation of low-molecular-weight protein tyrosine phosphatase (LMPTP) knockout mice combined with the identification of a small-molecule uncompetitive LMPTP inhibitor reveals a role for LMPTP in regulating insulin resistance.

GUIDE-seq (genome-wide unbiased identification of double-stranded breaks enabled by sequencing) is a sensitive, unbiased, genome-wide method for defining the specificity of genome-editing nucleases in living cells.

Richard Houlston and colleagues report a genome-wide association study for colorectal cancer. They report three loci newly associated with colorectal cancer, bringing the total number of common susceptibility loci to 20.