A CpG-A TLR9 Agonist Overcomes Resistance to PD-1 Blockade in Melanoma
See article, p. 2998.
Melanomas that lack CD8+ T cells or interferon signatures seldom respond to PD-1 blockade. Intratumoral injection of innate immune activators such as TLR9 agonists might induce interferon signatures and antitumor T cells, overcoming resistance to PD-1 blockade. In a phase Ib study, Ribas and colleagues administered vidutolimod, a virus-like particle containing a CpG-A TLR9 agonist, intratumorally along with intravenous pembrolizumab to 44 patients with advanced melanoma after PD-1 blockade. This combination demonstrated a manageable safety profile with clinical evidence of overcoming PD-1 blockade resistance, a 25% objective response rate, and durable regression of both injected and distant, noninjected tumors, including visceral metastases.
Comprehensive Genomic Sequencing Informs Understanding of Childhood Cancer
See article, p. 3008.
Genome-wide next-generation sequencing holds potential to enhance childhood cancer care but has not been routinely exploited to interrogate newly diagnosed as well as relapsed/refractory cases. Newman, Nakitandwe, Kesserwan, Azzato, Wheeler, and colleagues used whole-genome, whole-exome, and RNA sequencing to examine tumor and germline genomes from 309 children with approximately 80 subtypes of cancer through the Genomes for Kids protocol. Clinically relevant variants were identified in 86% of cases and new insights into tumorigenesis were gained from the discovery of novel somatic and germline variants, demonstrating comprehensive sequencing as an important modality in evaluating and managing the full spectrum of childhood cancers.
The PI3K/AKT Pathway Supports Lung Cancer Neuroendocrine Transformation
See article, p. 3028.
In lung adenocarcinomas amenable to targeted therapy, lineage plasticity can permit transformation to small cell lung cancer (SCLC) as a mechanism of acquired resistance. Defining molecular drivers of SCLC transformation has been limited by a paucity of paired samples for analysis. Quintanal-Villalonga and colleagues performed integrative multi-omic characterization of mixed histology and transforming cases, which together suggest that transformation is primarily driven by transcriptional reprogramming rather than mutational events. Enhanced activity of the PRC2 complex, PI3K/AKT, and NOTCH pathways was observed upon transformation. PI3K/AKT pathway inhibition delayed tumor growth and neuroendocrine transformation in an EGFR-mutant patient-derived xenograft model.
Mitochondrial DNA Offers Insight into the Clonal Evolution of CLL
See article, p. 3048.
Although mitochondrial DNA (mtDNA) mutations have the potential to serve as natural barcodes, their longitudinal kinetics are still poorly understood. Penter, Gohil, and colleagues leveraged a unique multimodal single cell assay (mtscATAC-seq) to read out mtDNA mutations alongside chromatin accessibility and copy number changes from serial chronic lymphocytic leukemia (CLL) samples from a range of clinical contexts. This demonstrated that changes to mtDNA mutations reflect the selective pressure exerted on leukemic cells during therapeutic bottlenecks, and furthermore, changes in chromatin accessibility and copy number aberrations can be linked to CLL cell populations marked by specific mtDNA mutations, affirming their utility as natural barcodes.
An AKT Degrader Reduces Growth of PI3K/PTEN-Mutant Cells by Lowering AURKB
See article, p. 3064.
AKT kinase inhibitors reduce growth of a portion of PI3K/PTEN pathway mutated cancer cell lines with wild-type KRAS/BRAF. Xu, Yu, and colleagues present a molecule, MS21, that preferentially degraded phospho-AKT and inhibited growth of 18 of 19 PI3K/PTEN pathway-mutant cell lines with intact KRAS/BRAF. Proteomic analysis determined that MS21 depleted AURKB, which led to the discovery that receptor tyrosine kinase/PI3K/AKT signaling regulates the stability of AURKB via AKT phosphorylation of AURKB on threonine 73. Growth inhibition by MS21 was dependent upon the destabilization of AURKB with this approach likely being beneficial in patients with PI3K/PTEN pathway mutations without RAS pathway mutations.
Induction of ERVs by Reactivated p53 Triggers Innate Immune Response
See article, p. 3090.
Although p53 has been found to repress endogenous retroviruses (ERV) to maintain genetic stability, Zhou, Singh, and colleagues found that pharmacologically activated p53 induces the expression of ERVs in cancer cells due to downregulation of ERV epigenetic silencers LSD1 and KDM1A. Concomitant synthesis of double-stranded RNAs (dsRNA) and induction of dsRNA sensors triggers an antiviral response pathway culminating in expression of antigen presentation and processing genes. Moreover, treatment with an MDM2 inhibitor increased the viral defense signature expression in patients with melanoma, and preclinical melanoma and colon cancer models showed enhanced tumor immunogenicity, T-cell infiltration, and sensitization to anti–PD-1 therapy.
Exogenous Cholesterol Is Essential to Clear Cell Renal Cell Carcinoma
See article, p. 3106.
Cholesterol accumulation, a universal feature of clear cell renal cell carcinoma (ccRCC), is of unclear significance for disease progression. Riscal and colleagues utilized integrative analyses of primary ccRCC tumors based on their transcriptomic, copy number variation, and metabolomic assays combined with public TCGA and proteomic data to reveal an apparent addiction of ccRCC cells to exogenous cholesterol and identify cholesterol transporters as a ccRCC vulnerability. Mendelian randomization analyses also revealed a causal link between elevated circulating HDL cholesterol and ccRCC risk. Accordingly, pharmacologic inhibition of SCARB1 (an overexpressed HDL cholesterol transporter) compromised ccRCC cell proliferation in vitro and in vivo.
A New PDX System Reproduces and Models Human Myelofibrosis In Vivo
See article, p. 3126.
Myelofibrosis (MF) is a largely incurable myeloproliferative neoplasm characterized by bone marrow fibrosis, leading to a median survival for patients of approximately five years along with a high propensity for transformation to almost uniformly lethal secondary acute myeloid leukemia (sAML). Therapeutic discovery for patients with MF has been hampered by the inability of murine models to replicate key patient pathologies. Here, Celik and colleagues present a new patient-derived xenograft system to model human MF that reproduces key human pathologies, is amenable to genetic and pharmacologic manipulation, and predicts patients with MF at risk for clonal progression to sAML.
WNT Signaling Potentiators Enhance Anticancer Immunity and Immunotherapy
See article, p. 3142.
Anticancer immune cells become dysfunctional in the tumor microenvironment, resulting in tumor progression and failure of immunotherapies. Seeking to identify factors that may boost immune cell activities, Tang and colleagues found that R-spondins, which are unique potentiators of WNT signaling, showed expression levels positively associated with the infiltration and functional status of natural killer (NK) cells and CD8+ T cells in tumors. These two types of immune cells prominently express the R-spondin receptor LGR6. In vivo experiments showed that R-spondin3 could inhibit tumor progression and enhance sensitivity to anti–PD-1 therapy, partly through enhancing MYC expression and ribosomal biogenesis in NK cells.
PI3K/p27Kip1 Is a Critical Node in Extrahepatic Biliary Cancer Tumorigenesis
See article, p. 3158.
Biliary tract cancer remains a lethal disease with little known about its molecular basis. Falcomatà, Bärthel, Ulrich, and colleagues developed a genetically engineered mouse model of bile duct cancer and, using genetic screening, showed that extrahepatic biliary epithelium is transformed upon Pik3caH1047R activation but not with oncogenic KrasG12D. Expression of the Pik3ca mutant induced invasive extrahepatic cholangiocarcinoma and PI3K-signaling output as well as repression of p27Kip1 were key determinants of tumor formation. Together, these studies provide insight for extrahepatic biliary cancer pathogenesis as well as demonstrates the tissue- and context-specific nature of cancer drivers.
A RON Isoform Drives Metastatic Outgrowth via Immune Suppression
See article, p. 3178.
Metastatic breast cancer is the overwhelming cause of death among patients with breast cancer, and the “immune-cold” nature of the disease is a barrier for immunotherapy. Lai, Gundlapalli, and colleagues showed that a specific isoform of RON receptor tyrosine kinase, short form RON (SF-RON), causes immune suppression and facilitates metastatic outgrowth in mice. Absence of SF-RON in the host microenvironment robustly augmented T cell–mediated immunity through accumulation of a stem-like CD4 T-cell subpopulation that enhanced tumor-specific CD8 T-cell responses. Treatment of mice with small-molecule inhibitors targeting RON also boosted antitumor immunity and protected from metastatic progression, suggesting therapeutic potential.
Mitochondrial Priming by NPM1c Sensitizes AML to Actinomycin D through PML
See article, p. 3198.
Actinomycin D has clinical efficacy in relapsed/refractory acute myeloid leukemias (AML) with NPM1c mutation, but the basis for therapeutic response remains incompletely understood. Wu and colleagues discovered that NPM1c impairs mitochondrial function and alters formation of PML nuclear bodies (NB), which are key senescence effectors and regulators of mitochondrial fitness. Actinomycin D targets these NPM1c-primed mitochondria, releasing mtDNA into the cytosol, and activates cGAS signaling, boosting ROS production, which ultimately restore PML NBs to drive senescence. Dual targeting of mitochondria by Actinomycin D and venetoclax exerts synergistic effects to clear NPM1c-AMLs in multiple ex vivo and in vivo models.
Rlf–Mycl Is a Fusion Oncogenic Driver in Small Cell Lung Cancer
See article, p. 3214.
Defining oncogenic drivers of small cell lung cancer (SCLC) remains necessary to develop critically needed therapeutics. Ciampricotti and colleagues developed the first Rlf–Mycl-driven mouse model of SCLC, as the fusion between these two genes is a recurrent genomic alteration in this disease. This gene fusion increased transformation, tumorigenesis, and tumor growth of SCLC cells as well as promoted metastasis to a multitude of different sites. Furthermore, tumors were found to be genomically consistent with their human counterparts. These characteristics suggest the use of these mice as preclinical models in the development of targeted therapeutic strategies for SCLC.