Volume 4 Issue 6, June 2023

Recent progress in melanoma treatment is based on research that poorly represents global population diversity, with little focus on relevant subtypes for non-European and admixed populations. However, there is an opportunity to change this and contribute to a more accurate understanding of melanoma worldwide.

Given the increasing use of immune-checkpoint inhibitors for treating cancer, immune-related adverse events — and markers to prevent and diagnose these — are coming into focus. A systematic analysis investigates genetic, molecular, cellular and clinical risk factors of such adverse events in a large pan-cancer cohort treated with multiple agents.

Successful immune-mediated tumor control in pancreatic cancer is severely hampered by its dense desmoplastic stroma. New work shows that EZH2 inhibition relieves the suppressive effect of tumor stroma on pro-inflammatory chemokine expression after therapy-induced senescence, boosting NK and T cell recruitment and immunological tumor control.

The discovery and approval of direct KRAS inhibitors for clinical use showed that mutant KRAS is not, as previously thought, an ‘undruggable’ oncoprotein. But therapeutic success is limited by the rapid onset of resistance. Two studies now show that YAP and TAZ represent an actionable target for tackling adaptive resistance to KRAS inhibitors.

Rebbeck, Huang and colleagues discuss recent insights into health inequities related to clinical next-generation sequencing for precision oncology, the contributing factors as well as recommendations for resolution looking ahead.

Green and colleagues discuss modes of cell death in cancer and focus on ‘near-death experiences’, whereby tumor cells engage the regulated cell death machinery yet survive, with far-reaching consequences for tumor survival, growth and therapy.

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.

Adachi et al. describe a mechanism of adaptive resistance to KRAS G12C inhibitors which involves a Scribble mis-localization via palmitoylation and subsequent YAP and MRAS activation that leads to feedback reactivation of MAPK signaling.

Sung et. al. identify genetic, molecular and clinical risk factors for immune-related adverse events in multicancer cohorts of patients treated with checkpoint inhibitors and develop predictive models that they validate in an independent cohort.

Zhou et. al. report the interim results of the randomized phase III GEMSTONE-302 trial, showing the overall survival benefits of first-line treatment with the PD-L1 inhibitor sugemalimab versus placebo in combination with chemotherapy, in patients with NSCLC.

Ruscetti and colleagues show that the pancreatic cancer tumor microenvironment suppresses immune surveillance following therapy-induced senescence via repression of inflammatory gene expression through EZH2.

Malladi and colleagues show that inhibiting DRP1 limits mitochondrial plasticity, resulting in increased mitochondrial fusion, impaired fatty acid oxidation and reduced metastasis formation in breast cancer models.

Joyce and colleagues use bulk and single-cell profiling of T cell phenotypes in human samples from primary brain tumors and brain metastases as a resource for understanding the biology and therapeutic relevance of the brain tumor microenvironment.