Reviews & Analysis

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  • The DNA polymerase Polθ is synthetic lethal with homologous-recombination deficiency, but a lack of specific targeting compounds has limited its therapeutic potential. Two studies now describe first-in-class inhibitors of Polθ with in vivo efficacy and thus provide alternative therapeutic approaches to PARP inhibitors for cancers deficient in homologous recombination.

    • Thomas Helleday
    News & Views
  • Scatiltri and colleagues review the paradigms of targeting PI3K in solid tumors in the clinic, including the progress so far in developing effective inhibitors as well as clinical limitations due to toxicity and therapeutic resistance.

    • Pau Castel
    • Eneda Toska
    • Maurizio Scaltriti
    Review Article
  • Mutations in genes encoding epigenetic modifiers are frequent in acute myelogenous leukemia (AML) and have been proposed to cause AML via activation of oncogenes and repression of tumor suppressors. Two studies now identify unexpected oncogenic mechanisms and therapeutic vulnerabilities in AML arising from mutations in genes encoding the epigenetic regulators DNMT3A and ASXL1.

    • Koki Ueda
    • Ulrich Steidl
    News & Views
  • Two recent studies demonstrate how autophagy, in both tumor cells and host tissues, regulates anti-tumor T cell responses. These works add to accumulating evidence that inhibitors of autophagy could be used in combination with immunotherapy in certain cancer types.

    • Andrew Thorburn
    • Christina G. Towers
    News & Views
  • Cancer cells need to adapt their metabolic state to different microenvironments, particularly during metastatic spread, when they are exposed to the circulatory system as well as the distant organ. Two studies now show that upregulation of fatty acid synthesis is required for the formation of breast cancer metastasis in the lipid-poor environment of the brain.

    • Felix C. E. Vogel
    • Almut Schulze
    News & Views
  • Small-molecule kinase inhibitors have made major advances in cancer therapy, but their efficacy remains limited by intrinsic and acquired resistance. The expression and thermostability of the kinase CDK6 are now shown to mediate intrinsic resistance to CDK4/6 inhibitors and degraders across cancer types.

    • Signe Caksa
    • Andrew E. Aplin
    News & Views
  • Passaro and colleagues discuss recent advances in treating EGFR-mutant lung cancer, including methods for detecting disease and tracking therapy response, developments in understanding of resistance mechanisms and ongoing clinical trials to circumvent therapeutic resistance to EGFR targeting.

    • Antonio Passaro
    • Pasi A. Jänne
    • Solange Peters
    Review Article
  • Pharmacogenomic drug screening provides a promising platform for the discovery of anti-cancer drugs, in combination with biomarkers and mechanisms that confer therapeutic response. A study now pinpoints the mechanisms of sensitivity to dasatinib in T-ALL leukemia, identifying a T cell–differentiation switch that determines sensitivity to distinct drug modalities.

    • Anders Jacobsen Skanderup
    • Ramanuj DasGupta
    News & Views
  • Shedding light on the mechanisms that underlie a durable response to immunotherapy, a recent study evaluating long-term survivors of melanoma treated with immunotherapy finds that tumor-associated T cell clonotypes are sustained over years and persist as expanded, cytokine IFN-γ–expressing resident memory T cells in the skin, with effector memory counterparts in the blood.

    • Anusha-Preethi Ganesan
    • Christian H. H. Ottensmeier
    News & Views
  • Kang and colleagues review recent advances and challenges in developing therapies for metastatic cancer and the clinical implications of ongoing and completed studies for metastatic disease.

    • Mark Esposito
    • Shridar Ganesan
    • Yibin Kang
    Review Article
  • Mukhopadhyay, Vander Heiden and McCormick review the metabolic landscape of RAS-driven cancers, the effects of RAS-directed metabolic reprogramming and opportunities for targeting these cancers therapeutically.

    • Suman Mukhopadhyay
    • Matthew G. Vander Heiden
    • Frank McCormick
    Review Article
  • The complexity of glioblastoma is becoming increasingly recognized. Three recent studies used single-cell approaches that integrate cellular states, transcriptional trajectories, and metabolic alterations to uncover multiple dimensions of cellular and molecular heterogeneity and provide a framework for additional functional investigation and therapeutic development.

    • Christopher G. Hubert
    • Justin D. Lathia
    News & Views
  • Metabolic reprogramming mediates resistance to therapy and rewires cancer-cell-signaling networks, paving the way to the discovery of enhanced treatment strategies through acquired vulnerabilities. A study now points to lipotoxicity dependent on Raf-1 kinase that occurs after activation of the liver receptor LXRα as a therapeutic intervention for the treatment of hepatocellular carcinoma.

    • Suchira Gallage
    • Jose Efren Barragan Avila
    • Mathias Heikenwalder
    News & Views
  • The diversity of tumor cell responses to cyclin-dependent kinase 4/6 (CDK4/6) inhibition in breast cancer is a question not yet fully addressed. A recent study defines the effects of CDK4/6 inhibition on chromatin organization and shows that remodeling of the cancer cell epigenome mediates some of the key biological effects of these targeted therapy agents.

    • Antoni Hurtado
    News & Views
  • Chronic pancreatitis is a risk factor for pancreatic cancer; however, the mechanisms underlying cellular susceptibility to oncogenic transformation are complex. A recent study reports a damage-associated progenitor cell state, controlled by the transcription factors KLF5 and members of the AP-1 family, that initiates tumorigenesis in mouse models of pancreatic cancer in which the proto-oncogene KRAS is altered.

    • Lindsay M. LaFave
    • Jason D. Buenrostro
    News & Views
  • Achieving depletion of regulatory T cells while sparing tumor-specific effector T cells has long remained an elusive goal of immunotherapy. A new study describing the development of an antibody to the cytokine receptor CD25 optimized to ensure depletion of regulatory T cells without blocking binding of the cytokine IL-2 will reinvigorate interest in this therapeutic avenue.

    • Gavin I. Ellis
    • James L. Riley
    News & Views
  • The response to immunotherapy has been linked to human leukocyte antigen (HLA) genotype in certain cancers. A new study examining the interaction between cancer type–specific mutational exposures and the B44 and B27 HLA supertypes finds that patients with mutant peptides complementary to these supertypes receive the most benefit from immune-checkpoint blockade.

    • Andrea Castro
    • Hannah Carter
    News & Views
  • Immunostimulatory agents such as Toll-like receptor (TLR) agonists have shown promising antitumor efficacy but are associated with therapy-related toxicities when delivered systemically. Immune-stimulating antibody conjugates are now shown to deliver TLR agonists with potent preclinical antitumor activities.

    • Olivier Demaria
    • Eric Vivier
    News & Views