Volume 6 Issue 2, February 2025

Although enhancing the GTPase activity of KRAS is an attractive approach to inhibit constitutively active, GTP-bound mutant KRAS, so far this has not been achieved. Now, a RAS inhibitor thought to act by preventing engagement of downstream effectors is shown to also reactivate cycling to the inactive GDP-bound state.

Targeting mitochondrial metabolic activity is an active area of cancer research. A study now finds that a selective deficiency in mitochondrial complex I in melanoma cells increases mitochondrial acetyl-CoA levels, leading to epigenetic activation of genes encoding antigen-presentation molecules that enhances tumor immunogenicity and boosts the efficacy of immunotherapy.

BRCA1 mediates homology-directed repair (HDR) of double-strand DNA breaks, explaining the sensitivity of BRCA1-deficient cancers to therapies that block DNA repair, while mutations that restore HDR cause therapy resistance. Research now reveals a mechanistically distinct vulnerability of BRCA1-deficient cancer cells to gap-inducing DNA nicks.

Mutations in ESR1, which encodes estrogen receptor-α (ERα), drive resistance to approved endocrine therapies in breast cancer. We studied the molecular response to the investigational ERα antagonist and degrader, giredestrant, in preclinical models and biopsy samples. We found that long-term inhibition or dysfunction of ERα result in cell plasticity with implications for therapeutic sensitivity.

McGaha and colleagues review recent research on the metabolic programs of tumor-associated macrophages across cancer types and discuss their implications on potential therapeutic vulnerabilities.

Marabelle et al. present updated data from the KEYNOTE-158 trial after ~4.5 years of follow-up, reporting an overall response rate of 34% and a median overall survival of 19.8 months in participants with MSI-H/MMR advanced noncolorectal solid tumors.

Rudalska et al. describe a novel class of p38α inhibitors with increased target residence time. They explore the drugs’ specificity, pharmacokinetics and toxicity profile and show that they are efficacious in the context of colorectal cancer.

Whalen et al. report that increased DNA end resection in BRCA-deficient, PARP inhibitor-resistant cancers leads to increased sensitivity to DNA nicks, limiting tumor formation in mice, and propose the therapeutic exploration of nickases.

Ritter et al. present a spatial transcriptomics and deep learning-based approach named NePSTA (neuropathology spatial transcriptomic analysis) and leverage it to improve neuropathological diagnostics and enhance central nervous system tumor subtype classification.

Keyl et al. present an explainable artificial intelligence model-based real-world data analysis from over 15,000 patients across 38 cancer types, identified key prognostic marker interactions, and confirmed these in an external lung cancer cohort.

Puigserver and colleagues show that genetic targeting of specific mitochondrial respiratory complex I subunits in melanoma and breast cancer cells boosts tumor immune surveillance via upregulation of antigen-processing and presentation components.

Jiang and colleagues identify ETV7 as a transcriptional node that skews CD8⁺ T cell transcriptional profiles toward exhaustion, consequently limiting antiviral and antitumor efficacy, and show that it can be targeted in CAR T cells to enhance efficacy.

Liang et al. study the impact of ERα antagonist/degraders against different Esr1 mutations in murine models and find that inhibition of mutant ERα induces lineage plasticity, which is also observed in Esr1-wild-type mice with long-term estrogen deprivation.

Shukla and colleagues study the genomic and transcriptomic data of exceptional responders to immunotherapy in renal cell carcinoma and find that such responses could be related to tertiary lymphoid structures, clonal neoantigen load and altered metabolism.

Panzeri et al. use a Trim28^+/D9 mouse model with intrinsic developmental heterogeneity to show that ‘heavy’ and ‘light’ developmental morphs exhibit different timing, type and severity of cancer, linked to a relevant DNA hypomethylation signature.