LBK1 Inactivation Modulates NSCLC Plasticity
LKB1 regulates energy homeostasis and is commonly mutated in non–small cell lung cancer (NSCLC). Li and colleagues report that Lkb1 (Stk11) loss in Kras-driven mouse models of NSCLC increased tumor heterogeneity, consisting of adenocarcinoma (AC), squamous cell carcinoma (SCC), and mixed tumors. This heterogeneity resulted from p63 (TRP63)-mediated AC to SCC transdifferentiation (AST). AC and SCC from mice and human samples exhibited different redox and metabolic signatures, likely driven by increased reactive oxygen species (ROS) accumulation in AC. Genetic activation of the NRF2 (NFE2L2)-dependent antioxidant program or small-molecule ROS scavengers attenuated AST in cell lines derived from the KrasG12D;Lkb1 knockout mice, suggesting that ROS modulates plasticity in NSCLC. The ROS-reducing drug phenformin attenuated AC, while increasing SCC in a ROS-dependent manner, consistent with phenformin-induced AST driving resistance.
Redefining Adult Lower-grade Glioma
Despite differences in approach and technique, three recent studies reached similar conclusions in molecular classification of lower-grade infiltrating glioma. The Cancer Genome Atlas (1) identified distinct biologic subsets based on unsupervised clustering of DNA methylation, gene expression, DNA copy number, and microRNA expression. These subgroups were recapitulated by codeletion of chromosome 1p/19q and mutations in IDH (mutations identified in either IDH1 or IDH2) and TP53. Eckel-Passow and colleagues (2) stratified tumors based on 1p/19q codeletion and mutations in IDH and the TERT promoter. Given the degree of intratumoral heterogeneity and tumor evolution demonstrated by Suzuki and colleagues (3) in lower-grade glioma, tumor stratification may not always be perfect. Indeed, small tumor subsets, such as the M1 cluster tumors with wild-type IDH1 and no TERT promoter mutations (1), may represent a distinct mechanism. Overall, the newly proposed strategy of tumor stratification greatly improves upon current methods and will hopefully lead to improved therapeutic options and outcomes for patients.
Ependymoma Classification
An increasingly granular view of the heterogeneity that exists within a given cancer diagnosis has been afforded through molecular profiling. Pajtler and colleagues used DNA methylation arrays to profile 500 ependymomas, including pediatric and adult cases and tumors resected from the brain (supratentorium and posterior fossa) and spine. They identified 9 distinct molecular subgroups. Remarkably, 2 subgroups in particular, including a group characterized by RELA fusions, were responsible for the vast majority of deaths due to this disease. In addition, these “high-risk” ependymomas mainly affected children and were largely unresponsive to chemotherapy and radiotherapy. This study thus identifies the unmet clinical need in ependymoma and offers a molecular framework to guide therapies and clinical trials moving forward.
Novel Antitumor Combination Therapy against Pancreatic Cancer
Sabutoclax is a small-molecule BH3 mimetic that inhibits the function of BCL2 proteins and induces growth arrest and apoptosis to variable extents in pancreatic cancer cells. Minocycline is a synthetic tetracycline that also has variable antitumor activity. Quinn and colleagues report that sabutoclax and minocycline in combination displayed pancreatic cancer–selective anticancer activity and caused robust mitochondria-mediated caspase-dependent cytotoxicity. Loss of phosphorylated STAT3 was a key player in this combinatorial synergistic effect, and reintroduction of activated STAT3 rescued cells from toxicity. The antitumor combination inhibited tumor growth and extended survival in both immune-deficient and immune-competent mouse models. These results support a novel combination of sabutoclax and minocycline as a potent combinatorial approach for inhibiting pancreatic tumor growth in preclinical animal models and inducing pancreatic cancer cell death both in vitro and in vivo.
Living Underneath a Quilt of Mutant Cells
In the prevailing view of cancer progression, a cell needs to acquire several genetic alterations to become cancerous and expands clonally at the expense of other cells. Martincorena and colleagues correct this view, demonstrating that sun-exposed normal skin carries a high burden of mutations in known drivers of cutaneous squamous cell carcinomas. Ultradeep sequencing of 74 cancer genes in small biopsies of normal skin revealed that the burden of somatic mutations in sun-exposed eyelids was similar to that in many cancers. The authors found that NOTCH1, NOTCH2, NOTCH3, TP53, FAT1, and RBM10 were already under strong positive selection, while FGFR3 had accumulated activating mutations. Overall, more than a quarter of normal skin cells carried a driver mutation. The physiologically normal epidermis was effectively a battlefield of hundreds of competing mutant clones in every square centimeter of skin.
Defining a Role for ALK Inhibition Across Cancers
As high-throughput sequencing approaches generate broad cataloging of genetic variations in cancer, we need to distinguish disease-causing or functionally relevant mutations from nonpathogenic passenger variants. Maxson and colleagues identify point mutations within the extracellular domain of the ALK receptor tyrosine kinase in 2 patients with acute leukemia (AML and B-ALL), broadening the role of this oncogene across cancers. Importantly, the investigators validate the functional relevance of these new mutations identified outside of the kinase domain and demonstrate their responsiveness to pharmacologic ALK inhibition. Future structural studies of the extracellular region of ALK will be necessary to provide insight into the impact of individual point mutations identified in this region in other tumors. The identification of oncogenic ALK point mutations in acute leukemia is unexpected and presents an exciting therapeutic opportunity in rare subsets of patients based on shared molecular etiology.
Note: Breaking Advances 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.
- ©2015 American Association for Cancer Research.
Volume 75, Issue 14
