Roychowdhury S, Iyer MK, Robinson DR, Lonigro RJ, Wu YM, Cao X, et al. Personalized oncology through integrative high-throughput sequencing: a pilot study. Sci Transl Medicine 2011;3:111ra121.The increasing availability of genomic technologies, coupled with a growing realization about the genetic complexity of individual malignancies, has led some to suggest that we should treat cancer as an essentially generic disease, analyzing each cancer for “targetable” mutations and personalizing medicine accordingly. To test the feasibility of this approach, Roychowdhury and colleagues set up a pilot project to identify patients, develop informed consent, analyze samples, identify relevant mutations, and implement all of this quickly and inexpensively. They performed whole-genome and transcriptome sequencing of tumor and targeted whole-exome sequencing of tumor and normal DNA. After feasibility was established, 2 test patients who had failed standard and secondary therapies were analyzed, both of whom had complex changes, and one of whom is reviewed below. Data analysis of this colorectal cancer identified 160 nonsynonymous somatic point mutations, 49 copy number abnormalities, 20 rearrangements, and 2 gene fusions. Lesions of likely relevance included an activating mutation in NRAS, homozygous inactivation of TP53, dual copy number gain and point mutation in Aurora kinase A, point mutations in smooth muscle myosin heavy chain and FAS death receptor, amplification of cyclin-dependent kinase (CDK)8, and copy number gains of epidermal growth factor receptor. Integrative copy number analysis revealed a large amplicon on chromosome 13 that included CDK8. RNA-Seq revealed an intrachromosomal gene fusion between acetylserotonin O-methyltransferase–like antisense RNA1 and protein phosphatase regulatory subunit 2. Members of a Sequencing Tumor Board discounted most of these findings for complex reasons, focusing on the NRAS and CDK8 mutations. The Board recommended a clinical trial with CDK or MAP kinase kinase inhibitors as well as inhibitors of phosphoinositide 3-kinase, none of which was actually available to this patient. Analysis took 3 to 4 weeks, with reagent cost of $5,400 at study start, dropping to $3,600 by the end of this study. This analysis establishes feasibility (but did not evaluate efficacy) for translating high-throughput sequencing into biomarker-driven clinical trials in cancer.Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 2011;20:576–90.Malignant cells communicate with other cells in their immediate microenvironment, generating signals that stimulate growth, resist apoptosis, suppress anticancer immune responses, and aid in extravasation. But what happens when malignant cells enter the bloodstream? Can cancer cells sense additional signals during transit through this dynamic new microenvironment? Labellle and colleagues show that direct interaction of malignant cells with platelets primes them for metastasis, inducing an epithelial-to-mesenchymal transition–like phenotype via synergistic activation of TGF-β/Smad and NF-κB pathways. This effect is independent of any contribution of platelets to immune surveillance or to physical shielding of malignant cells because metastatic potential can be enhanced by transient contact with platelets in vitro. Crucially, ablation of TFG-β in megakaryocytes and platelets inhibited metastases and prevented seeding of cancer cells to the lungs. These studies in mouse models are likely to be highly relevant to the human disease. For more than 10 years, we have known that many cancer patients have abnormally high platelet counts. In fact, nearly 40% of people with platelet counts exceeding 400,000/μL have an occult malignancy when further investigations are conducted. We could also speculate that the cancer-preventive effects of aspirin may in part be due to their actions on platelets. Platelets are interesting targets for antimetastatic therapies.Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M, et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 2011;334:1278–83.Cancer cells display a high level of oxidative stress due to oncogenic lesions such as activation of oncogenes or loss of tumor suppressors. During specific steps of tumorigenesis, cellular stress events such as hypoxia or matrix detachment lead to accumulation of reactive oxygen species (ROS). Cancer cells are particularly vulnerable to increases in ROS and must develop mechanisms for ROS detoxification for survival. One antioxidant response mechanism increases production of adenine dinucleotide phosphate (NADPH) via the pentose phosphate pathway. NADPH is an invaluable source of reducing agents that detoxify ROS. Anastasiou and colleagues show that, in A549 human lung cancer cells, increased intracellular levels of ROS cause inhibition of the glycolytic enzyme pyruvate kinase M2 (PKM2) through oxidation of the cysteine residue Cys358. Oxidation of PKM2 results in its diminished activity, leading to decreased pyruvate formation, increased diversion of glycolytic metabolites into the pentose phosphate pathway, and increased NADPH production. The authors show that a small molecule activator of PKM2, DASA-10, lowers the concentration of cellular reduced glutathione (GSH), decreasing the ability of cancer cells to tolerate exogenous H2O2. They further show that a nonoxidizable PKM2 mutant (where Cys358 was replaced with Ser358) impairs proliferation under hypoxic conditions in cancer cells. This proliferation defect can be restored after treatment with reduced GSH. Using a xenograft model, the authors show in vivo that lung cancer cells expressing the oxidation-resistant PKM2 mutant Ser358 form smaller tumors in mice compared with wild-type PKM2. These important results highlight a novel function for PKM2 not only in promoting metabolic changes required for proliferation but also in providing cancer cells with an additional mechanistic advantage to reduce oxidative stress, permitting their survival in acute oxidative stress conditions. Therefore, small-molecule activators of PKM2 coupled with standard treatments may prove beneficial as a therapeutic strategy.Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 2011;480:387–90.Resistance to RAF inhibitors, which is associated with increased RAF kinase activity, is an important problem in cancer therapy. Although RAF inhibitors show strong clinical activity in melanoma tumors harboring mutant BRAF, drug resistance inevitably overcomes the therapeutic benefits. Despite the clinical significance of this question, the mechanisms by which melanoma cells fail to respond to RAF inhibition are still poorly understood. Poulikakos and colleagues shed light on new mechanisms for drug resistance using the SKMEL-239 melanoma cell line harboring the BRAF mutant (V600E), which was exposed to a high dose of the RAF inhibitor vemurafenib. The authors discovered that a subset of cells resistant to vemurafenib express a new form of BRAF(V600E) lacking exons 4–8, the region that encodes the Ras-binding domain. Extracellular signal-regulated kinase signaling was resistant to vemurafenib activity when p61BRAF(V600E) was ectopically expressed. Furthermore, the authors demonstrate that deletion of these exons in p61BRAF(V600E) promotes dimerization of the protein compared with the full-length BRAF(V600E). Using the R509H dimerization-deficient mutation of p61BRAF(V600E), Poulikakos and colleagues show that RAF inhibitor resistance was the result of elevated p61BRAF(V600E) dimer formation. These findings are clinically significant, as out of a group of 19 multiple myeloma patients with acquired resistance to vemurafenib, 6 patients harbored splicing variants of BRAF(V600E) that lack the RAS-binding domain. This article shows one of the first resistance mechanisms that involves a direct structural change in BRAF, which would increase its dimerization even in the absence of Ras activation. This exciting article highlights the importance of alterations in the splicing machinery in cancer and drug resistance.Acquaviva J, Jun HY, Lessard J, Ruiz R, Zhu H, Donovan M, et al. Chronic activation of wild-type epidermal growth factor receptor and loss of Cdkn2a cause mouse glioblastoma formation. Cancer Res 2011;71:7198–206.Glioblastoma multiforme (GBM) is characterized by uncontrolled cellular proliferation, diffuse infiltration, and a tendency for hypoxia and necrosis that culminates in vigorous angiogenesis and an inherent resistance to therapeutic intervention. A key property of GBM is overexpression of the epidermal growth factor receptor (EGFR), which plays a critical role in GBM pathogenesis. This hypothesis is supported by the fact that wild-type EGFR and its ligands are overexpressed and activated in more than 65% of GBM tumors. An additional property of GBM is loss of the tumor suppressors Ink4a/Arf. Although previous efforts at modeling GBM using wild-type EGFR have not been successful, Acquaviva and colleagues now describe a novel mouse model of wild-type EGFR-driven gliomagenesis. Somatic conditional overexpression and ligand-mediated chronic activation of EGFR in combination with Ink4/Arf loss in the central nervous system of adult mice produces tumors reflecting the histopathologic and molecular properties of human GBMs. This model was used to evaluate the effect of EGFR tyrosine kinase inhibition and loss of PTEN expression on gliomagenesis. This interesting animal model could prove useful in providing insights into the molecular basis of GBM development and help in defining the effect of tyrosine kinase inhibition and other targeted therapeutic strategies for GBM.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.
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Dec 1, 2023
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