See article by Wang et al., p. 35

  • The first KRAS translocation is identified.

  • UBE2L3-KRAS transformed NIH3T3 cells and altered cellular signaling.

  • Ras-Raf-MAPK signaling is deregulated in prostate cancer metastasis.

Although KRAS is a commonly activated proto-oncogene, KRAS translocations have not been previously observed. Here, Chinnaiyan and colleagues use a method termed Amplification Breakpoint Ranking and Assembly (ABRA) to identify a fusion between the KRAS and UBE2L3 genes in the metastatic prostate cancer cell line DU145. KRAS rearrangements were also identified in a subset of metastatic prostate cancers. The UBE2L3-KRAS fusion includes most of UBE2L3 and all of KRAS, and it induced cell proliferation and focus formation when overexpressed in NIH3T3 cells. The fusion encouraged growth of tumor xenografts when these cells were implanted into nude mice. In addition, signaling was altered in these cells, with activation of AKT and p38 MAP kinase (MAPK) observed rather than the more typical activation of the MEK/ERK pathway. In prostate epithelial cells, the UBE2L3-KRAS fusion was transforming in vitro and in vivo and mislocalized to late endosomes. This work adds to a relatively short but growing list of fusion events discovered in solid tumors and suggests that deregulated RAS-RAF-MAPK signaling may play a role in metastatic prostate cancer.

See article by Kim et al., p. 44

  • A first step is taken toward personalized therapy for lung cancer.

  • The first prospective, biopsy-mandated, biomarker-based, adaptively randomized trial.

  • Integrates real-time molecular profiling for individualized treatment.

Lung cancer is the leading cause of cancer-related deaths in the United States. Systemic chemotherapy is the standard of care for metastatic lung cancer, but targeted treatments for lung cancer, unlike those for other cancers, have been only modestly effective due to the lack of predictive biomarkers. The novel design for the phase II Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial includes prospective tumor biopsy and uses adaptive randomization, based on tumor markers analyzed in real time, to assign patients with non–small cell lung cancer to the treatment with the greatest potential benefit. Kim and colleagues report a 46% 8-week disease control rate and establish the feasibility of a new paradigm for a personalized approach to lung cancer clinical trials.

See article by DeNardo et al., p. 54

  • T lymphocytes and tumor-associated macrophages (TAM) predicted better outcome.

  • Blockade of TAM infiltration improved sensitivity to chemotherapy and reduced tumor burden in mouse models.

  • Immunomodulatory agents may synergize with chemotherapies in treating breast cancer patients.

Recent work has shown that the immune microenvironment plays an important role in tumor biology. Here, Coussens and colleagues show that infiltration of certain types of leukocytes into breast tumor tissue predicts patient survival. In particular, high levels of CD8+ CTLs correlated with good outcome, whereas high levels of CD4+ T lymphocytes and TAMs correlated with poor outcome. Further, the authors found that the immune signature was predictive of relapse-free survival in patients whose disease had spread to their lymph nodes. Because such patients are often treated with chemotherapy, the authors hypothesized that the immune microenvironment might play a role in chemosensitivity. In a mouse model, they demonstrated that recruitment of TAMs was a common response of breast cancers to cytotoxic agents. The authors next demonstrated that treatment of tumor-bearing animals with antibodies or a small molecule that inhibited recruitment of TAMs resulted in improved sensitivity to chemotherapy as well as reduced primary tumor burden. This result also correlated with increased levels of CD8+ CTLs and a reduction in metastasis. Finally, the authors show that CD68 and CD8 levels predict response to chemotherapy in human patients. These data provide evidence that the immune microenvironment is critical in the response to chemotherapy and suggest that immunomodulatory agents that reduce recruitment of TAMs might improve sensitivity to chemotherapy.

See article by Platz et al., p. 68

  • Laboratory screening and epidemiology identify alternative use for digoxin.

  • Digoxin is a potent inhibitor of prostate cancer cell growth in vitro.

  • Digoxin users in the Health Professionals Follow-up Study had 25% lower risk of prostate cancer.

Is it possible to repurpose already-approved therapeutics for cancer prevention or treatment? Platz and colleagues tested over 3,100 compounds, 1,811 of which are FDA approved, in a high-throughput screen to determine their effectiveness in slowing the growth of prostate cancer cell lines. Among the agents not currently used as anticancer drugs, the class of cardiac glycoside Na+/K+ ATPase inhibitors showed strong inhibition of cell growth. This class includes digoxin, a drug commonly used to treat heart disease. The authors next examined the participants in the Health Professionals Follow-up Study, a large prospective cohort study on risk factors for chronic disease. From these data, they determined that users of digoxin had a 25% lower risk of prostate cancer than did nonusers. Although the mechanisms by which cardiac glycosides may serve as anticancer agents are not clear, this report suggests that further work is warranted. The article also provides elegant proof-of-principle that the combination of laboratory-based investigations with epidemiologic methods can be a powerful tool in translational science.

See article by Hammerman et al., p. 78

  • DDR2 kinase mutations identified in lung squamous cell carcinomas (SCC).

  • Mutant DDR2 is transforming in vitro and in vivo.

  • Dasatinib inhibits DDR2 in vitro and in vivo, suggesting clinical investigation.

Targeted therapies for lung adenocarcinoma have been clinically successful and are currently generating tremendous excitement. However, these existing therapies have little effect on lung SCCs. To identify new potential targets, Meyerson and colleagues performed sequencing of the tyrosine kinome, identifying mutations in the DDR2 kinase in 3.8% of lung SCCs and SCC cell lines. Dasatinib, an FDA-approved pharmacologic agent that inhibits multiple tyrosine kinases including DDR2, inhibited growth of cell lines harboring mutant DDR2, as did knockdown of the kinase. Overexpression of mutant DDR2 in cell lines resulted in classic features of transformation. To validate these results in vivo, the authors generated a xenograft model by injecting mice with cell lines harboring DDR2 mutations. Treatment of these mice with dasatinib decreased tumor size. In a clinical trial of erlotinib plus dasatinib, one patient harboring a mutation in DDR2 but with no mutation in epidermal growth factor receptor (the target of erlotinib) displayed a response. This suggests that further investigation of DDR2 inhibition as a clinical strategy in a subset of lung squamous cell carcinoma patients is warranted.

Note:In This Issue is written by Cancer Discovery Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.