AACR Project GENIE Surpasses 100,000 Patients
Using data from the over 100,000 patients currently included in the AACR Project GENIE registry, Pugh and colleagues performed updated comparisons to both The Cancer Genome Atlas and NCI-MATCH and demonstrated important differences that reflect the clinical context of the sequencing represented in GENIE. Importantly, the overall size of GENIE allowed for characterization of drug resistance mechanisms and rare populations, and the comparison with NCI-MATCH demonstrates the ability to use GENIE to provide a data-driven projection of trial enrollment and ultimately can be used to determine when populations are so rare that a trial may not be feasible.
ctDNA Dynamics Can Predict Alpelisib Benefit in Advanced Breast Cancer
The α-subunit–specific PI3K inhibitor alpelisib is an active agent in advanced breast cancer, but the clinical utility and biomarkers for patient selection are poorly defined in heavily pretreated disease. Savas, Lo, and colleagues conducted a phase II trial of alpelisib monotherapy in advanced breast cancer showing, in estrogen receptor–positive, HER2-negative cancers refractory to endocrine therapy, that the overall response rate was 30% and clinical benefit rate 36%. During therapy, dynamic changes in PI3K mutation levels detected via circulating tumor DNA (ctDNA) were predictive of benefit, as was the presence of ESR1 mutations at baseline.
Targeting Circadian Regulator ARNTL Restores Drug Sensitivity in Prostate Cancer
In a neoadjuvant phase II clinical trial, Linder, Hoogstraat, and colleagues describe extensive epigenomic reprogramming in prostate cancer upon androgen receptor (AR)–targeted therapy. Posttreatment tumor samples acquired certain features of neuroendocrine disease and activated signaling cascades to sustain viability despite therapeutic intervention. The circadian rhythm regulator ARNTL was found to drive tumor cell survival capacity and compensate for AR activity, representing an acquired drug-induced vulnerability. Perturbation of ARNTL expression in vitro and in vivo restored sensitivity to hormonal intervention, providing a promising therapeutic avenue for future clinical development in prostate cancer care.
Lineage Tracing Reveals Cryptic Functional Diversity in CAR T Cells
Although chimeric antigen receptor (CAR)–modified T cells are effective biotherapeutics for hematologic malignancies, they are typically evaluated in bulk, ignoring their inherent cellular heterogeneity. Wilson, Kim, and colleagues developed an integrative single-cell framework, using the T-cell receptor as a barcode to trace cellular lineages, and found that a small subset of CAR T cells with a unique cell-surface phenotype preferentially expand and persist as effectors after infusion. The study provides novel insight into CAR T-cell biology and sets the stage to explore opportunities to improve current CAR T-cell therapy approaches for a broad range of malignancies.
PRC2 Inactivation Enhances Therapeutic Efficacy of DNMT1 Inhibitors in Cancer
Novel therapeutics are needed in tumors in which polycomb repressive complex 2 (PRC2) is inactivated due to tumor suppressor activity. Through RNAi screening to identify vulnerabilities in the absence of PRC2 function, Patel and colleagues identified DNA methyltransferase 1 (DNMT1) and showed that PRC2 and DNMT1 coregulate silencing of retrotransposons. Consequently, selective inhibition of DNMT1 with small molecules (DNMTi) in PRC2-inactivated cancer cells leads to enhanced derepression of retrotransposons, viral mimicry signaling, and cell death through the double-stranded RNA sensor PKR. DNMTi therapy exhibits antitumor activity against PRC2-inactivated tumor models, indicating DNMT1 selective inhibitors as a therapeutic intervention for patients with PRC2-inactivated tumors.
IL-1β and TNFα Promote IL-8 Secretion in Multiple Tumor Types
IL-8 recruits immunosuppressive macrophages and granulocytes to the tumor microenvironment (TME) and is correlated with poor response to immune checkpoint inhibitors. Transcript levels of IL-8 are associated with transcript levels of both IL-1β and TNFα, but mechanisms of IL-8 control have not been fully defined. Olivera, Sanz-Pamplona, and colleagues indicated that both IL-1β and TNFα induce the transcription and secretion of IL-8 from multiple cancer cell types, which can be blocked by pharmacologic inhibition of IL-1β or TNFα, revealing a protumor axis of these cytokines. These results provide insight into mechanisms underlying TME-mediated immunosuppression and suggest targeting this axis in combination with checkpoint inhibitors.
SMYD3 Controls Small Cell Lung Cancer Sensitivity to Chemotherapy
Small cell lung cancer (SCLC) is the most fatal form of lung cancer, with limited therapeutic options and rapid development of chemoresistance. Lukinović, Hausmann, Roth, Oyeniran, and colleagues identified SMYD3 as a key regulator of SCLC sensitivity to alkylation-based chemotherapy. RNF113A methylation by SMYD3 blocks its inactivation by the phosphatase PP4, leading to a better alkylation damage response. The improved dealkylation repair induced by sustained RNF113A activity is responsible for increased SCLC tolerance to alkylation damage. Additionally, SMYD3 inhibition restores cancer cell vulnerability to alkylating chemotherapy, providing a rationale for targeting SMYD3 to improve SCLC responses to established chemotherapy.
Ferritinophagy Fuels Iron Metabolism for Pancreatic Adenocarcinoma
The cell-autonomous metabolic role of autophagy in pancreatic ductal adenocarcinoma (PDAC) has been studied in detail; however, the substrates that autophagy provides to support tumors remain unclear. Using preclinical models of PDAC, Santana-Codina and colleagues identify that NCOA4-mediated selective autophagy of ferritin, the cellular iron storage complex, is upregulated in PDAC to support iron metabolism for iron–sulfur cluster protein function. Targeting NCOA4 delays tumor progression and prolongs survival. These results align with data from patient cohorts in which a low ferritinophagy expression signature correlates with improved survival in patients with PDAC. This study defines NCOA4-mediated ferritinophagy as a therapeutic target in PDAC.
Ferritinophagy Disrupts RAS–MAPK Pathway Inhibition in Pancreatic Cancer
Increased dependence on autophagy confers protection against RAS-targeted therapy in pancreatic ductal adenocarcinoma (PDA), but the mechanisms underlying this adaptive response remain unclear. Ravichandran and colleagues showed that competition between MiT/TFE and c-MYC transcription factors controls the magnitude of autophagy and lysosome gene expression in PDA. Accordingly, downregulation of c-MYC following RAS–MAPK pathway inhibition leads to increased MiT/TFE-mediated autophagy and lysosome biogenesis. Proteomics of lysosomes isolated from MEK inhibitor–treated cells showed that increased ferritinophagy, a selective form of autophagy, supplies iron to fuel mitochondrial function and support PDA growth. Accordingly, blocking iron utilization enhanced the efficacy of MEK inhibition.