In This Issue
Journal: Cancer Discovery (2014)

See article, p. 662.Approximately 3% to 7% of non–small cell lung cancers (NSCLC) harbor chromosomal rearrangements of anaplastic lymphoma kinase (ALK) that lead to constitutive ALK activity and confer sensitivity to the ALK inhibitor crizotinib. Over half of patients with ALK-rearranged NSCLC initially respond to crizotinib, but resistance ultimately develops, often through ALK fusion gene amplification or secondary ALK mutation. Friboulet and colleagues evaluated the activity of ceritinib, a next-generation ALK inhibitor with higher selectivity and potency than crizotinib, in preclinical models of ALK-rearranged NSCLC. Ceritinib potently inhibited the growth of ALK-rearranged NSCLC cell lines in vitro and induced durable regressions of crizotinib-naïve ALK-rearranged NSCLC xenografts. Ceritinib also overcame crizotinib resistance in NSCLC cells in vitro and in vivo and potently inhibited the growth of cells expressing the most common secondary ALK mutations, although a couple of mutations conferred resistance to both crizotinib and ceritinib. Structural analyses of the ALK catalytic domain in complex with ceritinib revealed that the most common secondary ALK mutations that inhibit crizotinib binding are not predicted to adversely affect binding of ceritinib, though the rare mutations that remain ceritinib-resistant might sterically hinder ceritinib binding or change the conformation of the ALK catalytic domain. Consistent with these preclinical findings demonstrating the basis for the improved activity of ceritinib compared with crizotinib, ceritinib has shown strong activity in a phase I trial in crizotinib-naïve and crizotinib-refractory ALK-rearranged NSCLC, though these authors demonstrate that acquired resistance can be due to selection for the ceritinib-resistant secondary ALK mutations.See article, p. 674.Antibody blockade of the interaction between programmed death-1 ligand (PD-L1) on melanoma cells and programmed death-1 (PD-1) on T cells improves tumor immune surveillance and survival, but is less effective in patients whose tumors are poorly infiltrated by immune cells. Because immune cell infiltration is stimulated by inflammatory signals such as type I IFNs, Bald and colleagues investigated the role of type I IFN responses in melanoma immune surveillance. Analysis of primary melanomas revealed that low expression of a type I IFN response signature was associated with reduced relapse-free survival, suggesting that immune cell-poor melanomas escape type I IFN-mediated immune surveillance. Exposure of a mouse model of immune cell–poor melanoma, which showed low expression of type I IFN–responsive genes, to the immunostimulatory agent RNA polyinosinic:polycytidytic acid [poly(I:C)] markedly increased tumor expression of type I IFN–responsive genes, boosted immune cell recruitment, delayed tumor growth, and improved survival, but tumors ultimately progressed in association with compensatory PD-L1 upregulation. Administration of a PD-1 blocking antibody together with poly(I:C) provoked stronger immune cell infiltration, induced tumor regression, and enhanced host survival compared with poly(I:C) treatment alone. Importantly, PD-1 blockade alone was ineffective due to the lack of immune cell infiltration. Together with the observation that expression of IFN-responsive genes and PD-L1 are positively correlated with patient survival, these data suggest that targeted activation of type I IFNs in combination with PD-1 blockade may be an effective strategy to expose immune cell–poor melanomas to immune surveillance.See article, p. 688.Chronic pancreatitis is a risk factor for the development of pancreatic ductal adenocarcinoma (PDA), and pancreatic inflammation synergizes with mutant Kras to promote tumorigenesis in mice, but the underlying mechanisms are unclear. Baumgart and colleagues examined whether the transcription factor NFATC1, which is not expressed in normal pancreata but is induced in pancreatitis-associated human PDA, functionally cooperates with mutant KRAS in pancreatic carcinogenesis. Whereas Nfatc1 expression alone led to increased pancreatic cell proliferation but no precursor lesions or PDA, mice expressing both KrasG12D and Nfatc1 had significantly shortened survival and developed highly proliferative, invasive, and metastatic PDA. Gene signatures involved in transformation and inflammation such as the STAT3 pathway were enriched in cell lines generated from KrasG12D;Nfatc1 tumors, and NFATC1 was required for STAT3 induction and physically interacted with STAT3 in both human and murine PDA cells. Chromatin immunoprecipitation revealed that STAT3 recruited NFATC1 to regions distant to transcription start sites that overlapped with histone modifications characteristic of active enhancer regions. Together with the identification of EGFR, CCND3, and WNT family members as NFATC1–STAT3 targets, these findings suggest that NFATC1–STAT3 complexes operate at transcriptional regulatory elements and drive pancreatic cancer by activating an oncogenic gene network. Importantly, neoplastic transformation induced by inflammatory conditions in KrasG12D mice could be prevented by genetic or pharmacologic inhibition of NFATC1. These results indicate that inflammation-induced NFATC1–STAT3 complexes accelerate KRASG12D-mediated pancreatic carcinogenesis and reveal a potential chemopreventative strategy involving inhibition of NFATc1–STAT3 activity.See article, p. 702.Cancer cells that have undergone an epithelial-to-mesenchymal transition (EMT) play a key role in tumor metastasis and drug resistance, emphasizing the need for effective therapies that target this subpopulation. Feng and colleagues found that compounds with EMT-selective cytotoxicity induced ER stress and significantly upregulated expression of unfolded protein response (UPR) genes in mammary epithelial cells that had undergone an EMT. Established ER stressors more potently activated the UPR in EMT cells than in non-EMT cells, and induced apoptosis of both genetically-induced EMT cells and EMT-like breast cancer cell lines, implying that EMT confers sensitivity to ER stress. Interestingly, EMT cells displayed features characteristic of highly secretory cells and significantly upregulated secretion of extracellular matrix (ECM) proteins, suggesting that a high secretory output might increase ER stress sensitivity. Consistent with this finding, reducing the ER burden by depleting the proteins most highly secreted by EMT cells impaired activation of the UPR pathway induced by ER stressors. EMT cells constitutively activated the PKR-like ER kinase (PERK) branch of the UPR, and pharmacological inhibition of PERK blocked tumorsphere formation and inhibited EMT cell migration and mouse lung metastasis, indicating that the PERK pathway is required for the malignant phenotype of EMT cells. Notably, expression of EMT genes strongly correlated with PERK pathway-regulated genes in five independent datasets spanning over 700 diverse tumor types. Together, these results identify a vulnerability of EMT cells with potential therapeutic implications.See article, p. 716.Senescent cells produce a host of cytokines and other protumorigenic factors that are collectively referred to as the senescence-associated secretory phenotype (SASP). Cancer-associated fibroblasts (CAF) secrete many of the same proteins, raising the possibility that SASP regulators may represent stromal-specific therapeutic targets in tumors. Given that p38MAPK has been implicated in SASP regulation, Alspach and colleagues evaluated whether p38MAPK was required for the protumorigenic properties of the SASP. Indeed, p38MAPK inhibition led to downregulation of SASP factors and suppressed the protumorigenic activity of senescent fibroblasts. Mechanistically, p38MAPK enhanced mRNA stability by promoting the release of AU-rich RNA binding factor 1 (AUF1) from the 3′ untranslated region of SASP transcripts. Over 50 SASP factors were found to be p38MAPK dependent, many of which were found to be expressed in human breast cancer–associated stroma. As in senescent fibroblasts, p38MAPK was required for the protumorigenic activity of CAFs, raising the possibility that p38MAPK may represent a stromal-specific therapeutic target in both senescent and nonsenescent fibroblasts. The authors found that administration of the p38MAPK-specific inhibitor CDD-111 significantly reduced SASP factor expression in senescent human fibroblasts injected into mice and markedly reduced the ability of senescent fibroblasts or primary CAFs to initiate or maintain xenograft tumor growth. Together, these results demonstrate p38MAPK-mediated post-transcriptional regulation is required for maintenance of the SASP and suggest that inhibiting p38MAPK may represent a strategy to target the tumor microenvironment and limit tumor growth.See article, p. 730.Sorafenib, a multikinase inhibitor that targets VEGFRs, improves survival in patients with advanced hepatocellular carcinoma (HCC), but responses are limited and toxicity can be significant. Given that inflammatory signaling promotes tumor growth and survival, Horwitz and colleagues analyzed inflammation-induced HCCs in an Mdr2−/− mouse model for recurrent genetic aberrations that might represent additional therapeutic targets. Interestingly, the authors identified frequent amplification of chromosome 17, which harbors Vegfa, and identified gain of the corresponding locus in 11% of human HCCs. Amplification-positive tumors were characterized by high VEGFA expression and increased proliferation, vascular density, and macrophage infiltration. Macrophages found in Vegfa-amplified tumors expressed high levels of hepatocyte growth factor (HGF), suggesting that prosurvival hepatocyte–endothelial cell crosstalk may drive tumor cell proliferation. In support of a non–cell-autonomous role of Vegfa amplification, macrophages isolated from Mdr2−/− dysplastic livers expressed higher levels of VEGFRs whereas expression of the HGF receptor (c-MET) was higher in hepatocytes. Importantly, inhibition of VEGFA specifically reduced HGF expression and inhibited tumorigenicity of Vegfa-amplified cells in vivo, and forced VEGFA expression in human HCC xenografts induced macrophage HGF expression and promoted tumor growth. Notably, a retrospective analysis revealed an overall survival advantage of sorafenib treatment in patients with VEGFA-amplified HCC compared with patients without amplification. These results suggest that VEGFA amplification may promote HCC through paracrine interactions with the tumor microenvironment and indicate that VEGFA gain may be a predictive biomarker of sorafenib response.Note: In This Issue is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details.