Highlights from Recent Cancer Literature
Journal: Cancer Research (2021)

Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL) are both non-Hodgkin lymphomas of B-cells that share features such as hyperactivation of the MYC oncogene due to translocation events, but the other genetic events that are shared between these diseases are not fully understood. Gong and colleagues showed that DDX3X loss-of-function mutations, which disrupt the function of an important RNA helicase, were recurrent in both Burkitt lymphoma as well as in MYC-driven DLBCL. The authors then investigated the significance of DDX3X mutations in both early lymphoma development and after tumors were established. Initially, loss of DDX3X is protective against MYC-induced stress by limiting translation and protein synthesis, and unexpectedly, the authors observed that fully transformed lymphoma cells upregulate expression of the DDX3X homolog DDX3Y in order to restore full capacity of the translation machinery.Expert Commentary: This study proposes an appealing approach for treatment of MYC-driven lymphoma based on compounds either targeting DDX3Y or that interfere with the equilibrium between translation and proteotoxic stress.Gong C, Krupka JA, Gao J, Grigoropoulos NF, Giotopoulos G, Asby R, et al. Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis. Molecular Cell; Published online August 18, 2021: DOI: 10.1016/j.molcel.2021.07.041.The combination of CDK4/6 inhibitors (CDK4/6i) with antiestrogen therapy is the standard-of-care treatment for hormone-positive breast cancer. However, only a portion of patients respond and acquired resistance is almost inevitable. Freeman-Cook and colleagues utilized both patient samples and preclinical models to demonstrate that increased expression of CDK2/cyclin E and MYC led to resistance. They developed and optimized a novel potent CDK2/4/6i, PF-06873600, which had significant activity in CDK4/6i resistance models, especially when MYC or cyclin E was overexpressed. Furthermore, PF-06873600 in combination with immunotherapy enhanced antitumor immunity.Expert Commentary: The authors demonstrated the key role of CDK2 inhibition in preventing and overcoming CDK4/6i resistance and developed a novel CDK2/4/6i, which is being tested in the clinic.Freeman-Cook K, Hoffman RL, Miller N, Almaden J, Chionis J, Zhang Q, et al. Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor. Cancer Cell; Published online September 11, 2021; DOI: 10.1016/j.ccell.2021.08.009.One key feature of the tumor microenvironment in clear cell renal cell carcinoma (ccRCC) is the presence of peripheral white adipose tissue (PAT), which is important for normal kidney function, but also represents a site that tumor cells frequently invade into. This event has been associated with worse prognosis for patients, but the benefits that ccRCC tumor cells gain from PAT remains an open question. Wei and colleagues first demonstrated that ccRCC cells induce browning of PAT by secreting parathyroid hormone-related protein, which is dependent on PKA activity, and these beige adipocytes then support tumor cell growth and invasion through increased lactate secretion. The authors also provided a link between this crosstalk event with drug resistance by demonstrating that tyrosine kinase inhibitors (TKI) also increase adipocyte browning, and subsequent experiments showed that TKI therapy could be improved in combination with PKA inhibitors.Expert Commentary: These findings provide a mechanistic explanation of how tumor cells and adipose tissue impact one another within the tumor microenvironment and suggest that TKIs in combination with antithermogenic drugs could treat ccRCC.Wei G, Sun H, Dong K, Hu L, Wang Q, Zhuang Q, et al. The thermogenic activity of adjacent adipocytes fuels the progression of ccRCC and compromises anti-tumor therapeutic efficacy. Cell Metabolism; Published September 28, 2021; DOI: 10.1016/j.cmet.2021.08.012.While targeted therapies have significantly improved prognosis for patients with HER2+ breast tumors, resistance develops frequently, and toxicity remains a major obstacle. While studying the structure of HER2, Faure and colleagues identified a binding motif that facilitates the interaction between HER2 and ezrin/radixin/moesin (ERM) family members, which was not shared by other EGFR family members and functionally results in decreased HER2 activity. ERM proteins were found to have reduced expression in HER2+ breast cancers, so the authors performed a screen for compounds that could mimic the function of ERM in binding to and repressing HER2 as a novel therapeutic treatment for this disease. Zuclopenthixol was identified as a promising candidate and was able to reduce HER2 activity and suppress the growth of both primary breast tumors and brain metastases in mouse models.Expert Commentary: This study highlights a new regulatory mechanism of HER2 by the ERM family members and demonstrates a novel approach to targeting the HER2 protein in the treatment of breast cancer.Faure C, Djerbi-Bouillié R, Domingot A, Bouzinba-Segard H, Tauji S, Saidi Y, et al. Allosteric inhibition of HER2 by Moesin-mimicking compounds targets HER2-positive cancers and brain metastases. Cancer Res 2021;81:5464–76.Checkpoint blockade of immune inhibitory receptors such as Tim-3 boosts the activity of antitumor CD8+ T cells, but Tim-3 is also expressed on a subset of T regulatory cells (Tregs) and the impact of Tim-3 blocking antibodies on this cell type is unknown. Banerjee and colleagues revealed that Tim-3 was expressed to a greater extent on tumor-infiltrating Tregs as compared with CD8+ T cells in tumors and was also induced in tumor-draining lymph node Tregs. Tim-3+ Tregs had an activated phenotype and expressed high levels of the immunosuppressive cytokine IL10 and extracellular adenosine-generating machinery. By conditionally overexpressing Tim-3 specifically in Tregs, they showed that Tim-3 increased Treg frequency in lymphoid tissues and drove growth of transplanted tumors. Tim-3–overexpressing Tregs were more activated, switched from oxidative phosphorylation toward glycolytic metabolism, and proved more suppressive in vitro. Conversely, conditional deletion of Tim-3 in Tregs led to stronger tumor control, with fewer Tregs in tumors as well as decreased IL10 production.Expert Commentary: Tim-3 signaling in Tregs directly regulated immunosuppression and likely contributes to the activity of Tim-3–targeted checkpoint blockade immunotherapies for cancer.Banerjee H, Nieves-Rosado H, Kulkarni A, Murter B, McGrath KV, Chandran UR, et al. Expression of Tim-3 drives phenotypic and functional changes in Treg cells in secondary lymphoid organs and the tumor microenvironment. Cell Rep 2021;36:109699. DOI: 10.1016/j.celrep.2021.109699Radiation-induced gliomas (RIG) are a devastating complication of radiotherapy for childhood malignancies, but the genetic events that initiate this disease have not been explored previously. Deng and colleagues (1) and DeSisto and colleagues (2) separately assembled cohorts of 31 and 32 RIGs, and performed genome-wide methylation profiling, with gene expression and DNA sequencing where available. Medulloblastoma and acute lymphocytic leukemia comprised the original diagnosis in the majority of RIGs. Methylation profiles were highly consistent with IDH1 wild-type tumors, and copy number landscapes revealed recurrent PDGFRA amplifications with CDKN2A loss. Compared with other pediatric high-grade gliomas, chromothripsis and BCOR deletions were enriched, and RIG clustered distinctly by gene expression. Several RIGs harbored activating fusions in MET, NTRK, and RAF1, suggesting potential actionability. A drug screen of two cell lines derived from RIG suggested potential activity for MEK inhibitors, microtubule inhibitors, DNA damaging agents, and proteosome inhibitors.Expert Commentary: These two studies provide insights into the unique RIG molecular profile. Although prevention of RIG through upfront radiation-sparing approaches is the ideal strategy, these two studies suggest that targeted therapies should be considered.1. Deng MY, Sturm D, Pfaff E, Sill M, Stichel D, Balasubramanian GP, et al. Radiation-induced gliomas represent H3-/IDH-wild type pediatric gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B. Nat Commun 2021;12:5530. DOI: 10.1038/s41467-021-25708-y.2. DeSisto J, Lucas JT Jr, Xu K, Donson A, Lin T, Sanford B, et al. Comprehensive molecular characterization of pediatric radiation-induced high-grade glioma. Nat Commun 2021;12:5531. DOI: 10.1038/s41467-021-25709-x.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.