Bresler and colleagues characterize mutations in anaplastic lymphoma kinase (ALK), a cell surface receptor tyrosine kinase, in neuroblastoma. Among 1,596 patients, 8% showed at least one mutation. Mutations in three residues (R1275, F1174, and F1245) accounted for 85% of the identified mutations. Copy number gain was mutually exclusive with mutation. Multivariable analysis showed that ALK mutation was an independent predictor of poor survival. F1174 mutations were over-represented in MYCN-amplified tumors, and patients with both mutations had very poor outcomes. Biochemical studies showed that mutant alleles activated tyrosine kinase domain autophosphorylation. A close correspondence was identified between transforming potential and in vitro–determined kcat values for autophosphorylation. Overall, these results suggest that ALK is a biomarker of disease status in neuroblastoma and provide clinical information to guide therapy.Bresler SC, Weiser DA, Huwe PJ, Park JH, Krytska K, Ryles H, et al. ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell 2014;26:682–94.Profiling the expression of long noncoding RNAs (lncRNA) in breast cancer, Xing and colleagues found that expression of the lncRNA BCAR4 correlated inversely with survival in advanced breast cancer. BCAR4 binds directly to both Smad nuclear-interacting protein 1 (SNIP1) and a protein phosphatase 1 regulatory subunit (PNUTS, PPP1R10) and indirectly to GLI2 and Citron Rho-interacting kinase (CITK, CIT). The cytokine CCL21 induces GLI2 phosphorylation on S149 and nuclear translocation in a manner dependent on CITK. GLI2 S149 induced binding to SNIP1, releasing SNIP1's repression of p300-mediated histone acetylation and increasing H3K18 acetylation on GLI2 target genes. PNUTS was in turn recruited to promoters of GLI2 target genes, where it attenuated PP1 phosphatase activity, relieving inhibition of RNA Pol II via increased phosphorylation of its carboxyl terminal domain. The BCAR4 complex regulated cancer cell migration in vitro and suppressed breast cancer metastasis in mouse models.Xing Z, Lin A, Li C, Liang K, Wang S, Liu Y, et al. lncRNA directs cooperative epigenetic regulation downstream of chemokine signals. Cell 2014;159:1110–25.Expression of βIII-tubulin (TUBB3) is associated with therapeutic resistance and aggressive non–small cell lung carcinoma (NSCLC); however, the molecular mechanisms of βIII-tubulin-mediated tumorigenesis are unknown. McCaroll and colleagues determined that βIII-tubulin regulates the expression of proteins associated with malignant growth and metastasis in NSCLC. Of importance, βIII-tubulin differentially regulated the tumor suppressor maspin (SERPINB5). Silencing the expression of βIII-tubulin caused alteration in cell morphology, reduced outgrowth of tumor spheroids, and increased sensitivity to detachment-based killing (anoikis). Additionally, βIII-tubulin regulated the PTEN/AKT signaling pathway in NSCLC. Blocking βIII-tubulin in vivo reduced lung tumor incidence and growth in two mouse models. Thus, the authors have identified a mechanism by which βIII-tubulin influences tumor growth in NSCLC.McCarroll JA, Gan PP, Erlich RB, Liu M, Dwarte T, Sagnella S, et al. TUBB3/βIII-tubulin acts through the PTEN/AKT signaling axis to promote tumorigenesis and anoikis resistance in non-small cell lung cancer. Cancer Res; Published OnlineFirst November 20, 2014; doi:10.1158/0008-5472.CAN-14-2740.PD-L1 (CD274) is the ligand for PD-1 (PDCD1), a negative regulator of T-cell activation that restricts tumor cell killing. Herbst and colleagues designed an innovative phase I study of PD-L1 inhibition using a high-affinity PD-L1 antibody (MPDL3280A) on 277 patients with incurable cancer. No maximum tolerated dose was identified and toxicity was minimal. Objective and durable responses were observed in a substantial subset of the patients. A noted association between response and expression of PD-L1 on tumor-infiltrating immune cells (in pretreatment samples) was far stronger than the association with PD-L1 expression in tumor cells. Serial on-treatment biopsies revealed upregulation of PD-L1 by tumor cells in responders, suggesting that tumor-infiltrating immune cells may preferentially suppress preexisting T-cell responses before therapy. Larger studies are needed to validate these compelling observations, and careful understanding of nonresponders will likely provide key insights.Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515:563–7.Ras-related protein RALA and RALB proteins are GTP-binding proteins that signal downstream of RAS in cancer. To develop small molecule inhibitors of RAL, Yan and colleagues performed a structure-based virtual screen to identify small molecules that selectively bind to GDP-bound RALA at a site distinct from the guanine nucleotide binding pocket. The compound BQU57 was shown by isothermal titration calorimetry, surface plasmon resonance, and 1H–15N transverse relaxation-optimized spectroscopy NMR spectroscopy to bind to RALB. Two allosteric compounds, RBC8 and BQU57 (IC50, 1.3–3.5 μM), showed growth blockade in lung cancer xenografts in vivo, and also blocked RALA and RALB in vivo. These agents, which are being developed in collaboration with NantBioScience, represent a first-generation set of compounds to target RAL proteins in cancer.Yan C, Liu D, Li L, Wempe MF, Guin S, Khanna M, et al. Discovery and characterization of small molecules that target the GTPase Ral. Nature 2014;515:443–7.Oncogenic mutations in H3F3A, encoding the histone variant H3.3A, are common in malignant pediatric glioma, including diffuse intrinsic pontine glioma. The K27M mutant H3.3 results in a global reduction of the repressive histone mark H3K27me3 due to sequestering of the polycomb repressive complex 2 (PRC2). Hashizume and colleagues demonstrate that pharmacologic inhibition of the K27 demethylase JMJD3 (KDM6B) with GSKJ4 increased cellular H3K27 methylation and was associated with decreased cell viability, increased apoptosis, and decreased clonal growth exclusively in cells with the K27M mutation. SiRNA knockdown of JMJD3 also resulted in inhibition of cell growth, and this was not further augmented by GSKJ4 treatment. Subsequent treatment of mice harboring subcutaneous and intracranial K27M xenografts demonstrated decreased tumor growth and prolonged survival.Hashizume R, Andor N, Ihara Y, Lerner R, Gan H, Chen X, et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med 2014;20:1394–6.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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