Reviews & Analysis

We sought to develop a pharmacologically advanced inhibitor of the oncoprotein RET. Vepafestinib potently inhibited on-target mutants that confer resistance to approved RET inhibitors while exerting superior efficacy against intracranial disease due to enhanced penetration and retention in the brain.

Resected pancreatic cancer treated pre-operatively with chemotherapy is enriched for cells that co-express GATA6, KRT17 and CYP3A. Persistent expression of GATA6^hi and KRT17^hi is associated with poor survival after treatment with mFOLFIRINOX, but not gemcitabine. CYP3A-expressing drug detoxification pathways metabolize the prodrug irinotecan, a constituent of mFOLFIRINOX, leading to persistent drug tolerance.

Immunosuppressive myeloid cells, which are associated with resistance to anti-PD1 therapy in patients with glioblastoma, have high expression of KDM6B, an epigenetic enzyme. Deletion or inhibition of KDM6B reprograms the myeloid cells to an immunostimulatory phenotype and thereby overcomes resistance to anti-PD1 therapy in preclinical models of glioblastoma.

Treatment with immune checkpoint inhibitors (ICIs) has improved the survival of patients with metastatic melanoma. However, although ICIs are promising for achieving lasting clinical responses, only a subset of patients receive substantial benefit. Our results suggest that the IL-17 pathway supports the response of melanoma to dual ICI therapy and might represent a biomarker for patient stratification.

This study reveals the previously underappreciated roles of CD25 (IL-2 receptor subunit-α) in IL-2 biology and cancer immunotherapy and provides mechanistic insights into the rational design of more-effective IL-2-based therapeutic agents for cancer treatment.

Tyrosine kinase inhibitors that target anaplastic lymphoma kinase (ALK) have greatly improved the survival of patients with ALK-rearranged non-small-cell lung cancer, but they are insufficient to achieve a complete cure. A newly developed vaccine elicited a strong immune response specifically against ALK that eradicated primary tumors and prevented the onset of metastatic disease in mice.

Chimeric antigen receptor (CAR) T cells are effective for the treatment of therapy-resistant blood cancers but not solid tumors. We used a well-studied mutant c-KIT protein (c-KIT D816V) as a co-stimulatory domain to generate CAR T cells with strong IFNγ signaling that were able to overcome the immunosuppressive microenvironment of solid tumors.

An antisense RNA, NQO1-AS, binds and stabilizes its sense strand, upregulating the redox enzyme NQO1 in metastatic breast cancer cells. Overexpression of NQO1 facilitates lung colonization by suppressing oxidative stress and ferroptosis, and cancer cells dependent on this pathway can be targeted by a combined therapy that induces ferroptosis while simultaneously inhibiting NQO1.

Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy. We examined the dynamic changes of immune cells that occur in the tumor microenvironment of radio-immunotherapy-treated glioblastomas and identified a subpopulation of regulatory T cells with increased immunosuppressive activity. Depletion of this cell population improved survival in a mouse model of glioblastoma.

Multiple myeloma is a rare and incurable cancer of plasma cells. To characterize this cancer, we developed an ex vivo drug screening method that combines imaging, deep learning and multiomics and applied it in an observational trial, uncovering new potential therapeutic strategies and underlying disease mechanisms.

Lobular breast cancer is the second most prevalent breast cancer subtype, but clinical trials have not focused on these patients. The GELATO study reveals the feasibility of trials that are specific for this difficult to treat cancer and indicates that patients with lobular breast cancer can benefit from immunotherapy using PD-L1 blockade.

A study of the immune microenvironment of estrogen receptor-positive (ER⁺) invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) identifies pro-tumor and anti-tumor macrophages as key players that can potentially influence disease outcome.

High-fat diet and the secretome of breast tumors prime distant organs for metastasis formation. During lung priming, alveolar type II cells increase the release of palmitate, which is oxidized to acetyl-CoA by metastasizing breast cancer cells, where the increased acetylation of the NF-κB subunit p65 activates a pro-metastatic transcriptional program.

Using an unbiased algorithm based on kinase–phosphorylation site interactions that is applicable to any proteomic dataset, we identified and experimentally validated two protein kinases (PKCδ and DNA-PKcs) as the master kinases that drive two functional subtypes of glioblastoma multiforme and are potential therapeutic targets of other cancer subtypes.

Somatic mutations in cancer genomes are caused by multiple mutational processes, each generating characteristic mutational signatures. Our systematic mutational signature analysis of single base substitutions and small insertions and deletions in pediatric cancers indicates that the contribution of signatures of homologous recombination repair defect is limited and identifies a leukemia-specific signature.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of mortality worldwide. Integrative analysis of the genome, transcriptome and proteome of PDAC tissues, also known as proteogenomic analysis, provides insight into the biology of this cancer and is a resource for therapeutic discovery.

Modulation of T cell immune checkpoints combined with inhibition of chemokine receptors on myeloid-derived suppressor cells can reprogram the highly suppressive tumor immune microenvironment of pancreatic ductal adenocarcinoma (PDAC), and generates durable complete responses in a PDAC mouse model. These results provide a testable clinical regimen for human PDAC.