Konopleva and colleagues present results of a phase 2 single arm study evaluating venetoclax, an oral BCL-2 inhibitor, in patients with relapsed/refractory acute myelogenous leukemia. Objective response rate was 19% (6/32), with an additional 19% of patients showing partial responses. Notably, 27% of patients with a BCL-2–family-sensitive protein index, defined as ≥35% of tumor cells expressing BCL-2 and <40% of tumor cells expressing BCL-XL, underwent longer duration of therapy with venetoclax. BH3 profiling identified samples with the most BCL-2 dependence and sensitivity to BCL-2 inhibition. Unlike patients with chronic lymphocytic leukemia, dependence on BCL-2 was not sufficient for durable clinical benefit. The objective activity with a well-tolerated single oral agent was notable in a disease notorious for responding only to dose-intensive chemotherapy. Additional studies will need to refine biomarkers to identify patients who may benefit from BCL-2 inhibition.

Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discovery; Published OnlineFirst August 12, 2016; doi: 10.1158/2159-8290.CD-16-0313.

Mortality in epithelial cancers is usually caused by metastasis. Extravasation is the critical step of cancer cells leaving blood vessels to initiate dissemination. Strilic and colleagues demonstrate that cancer cells enforce endothelial cell death to facilitate transendothelial migration. In cells and endothelial-specific transgenic mouse models, programmed cell necroptosis and not apoptosis was the mode of endothelial cell death. Tumor cell-induced endothelial cell necroptosis was mediated by physical interaction between endothelial cell death receptor 6 and tumor cell amyloid precursor protein ligand. Questions remain as to mechanism. Does the endothelial cell necroptosis simply generate a gap in the endothelium or do dying endothelial cells signal to direct the extravasation? Regardless of the precise mechanism, these provocative data highlight a novel potential targetable pathway to mitigate the metastatic cascade by blocking extravasation.

Strilic B, Yang L, Albarrán-Juárez J, Wachsmuth L, Han K, Müller UC, et al. Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. Nature 2016;536:215–8.

Overexpression of the lysine methyltransferase EZH2 in non-small cell lung carcinoma (NSCLC) is associated with a poor outcome. Zhang and colleagues, overexpressing EZH2 in human immortalized bronchial epithelial cells, observed transformation. Reduction of EZH2 levels in human lung adenocarcinoma cells that overexpressed EZH2, but harbored no other obvious oncogenic drivers, reduced tumor cell viability in vitro and reduced growth in xenografts. Further, genetically engineered mouse models that overexpressed wild-type EZH2 in the lung developed adenocarcinoma, with increased H3K27me3 at tumor suppressor loci. These murine lung adenocarcinomas elaborated a transcriptional program distinct from that of KRAS mutant mouse lung adenocarcinoma. A similar gene expression signature identified a subset of human NSCLCs that overexpressed EZH2. EZH2 inhibition was also able to attenuate the growth of EZH2-overexpressing lung adenocarcinomas in mice. This is the first demonstration of the oncogenic potential of wild-type EZH2 in vivo.

Zhang H, Qi J, Reyes JM, Li L, Rao PK, Li F, et al. Oncogenic deregulation of EZH2 as an opportunity for targeted therapy in lung cancer. Cancer Discov 2016;6:1066-21.

N-myc has been previously suggested as a substrate of the ubiquitin-specific protease USP7/HAUSP. To examine this relationship, Tavana and colleagues examined the Nes-Cre;Hauspfl/fl mouse and found markedly decreased levels of N-myc in E13.5 murine developing forebrain, independent of p53. Coimmunoprecipitation studies and overexpression of both mutant and wild-type N-myc revealed that N-myc was a bona fide substrate of HAUSP. HAUSP knockdown impaired growth of MYCN-amplified but not MYC-amplified cells and did not deplete levels of MYC. In neuroblastoma, higher HAUSP levels correlated with poorer outcome. Pharmacological inhibition of HAUSP resulted in significantly smaller tumors in MYCN-amplified but not in non-MYCN-amplified orthotopic mouse models. These observations suggest small-molecule inhibition of HAUSP as a rational treatment strategy for MYCN-amplified tumors.

Tavana O, Li D, Dai C, Lopez G, Banerjee D, Kon N, et al. HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma. Nat Med 2016 Sep 12. doi: 10.1038/nm.4180. [Epub ahead of print].

Hepatocellular carcinoma (HCC) accounts for 90% of all liver cancers and is the second leading cause of cancer-related mortality worldwide. Ye and colleagues identified Golgi membrane protein 1 (GOLM1) as a major regulator of HCC tumor growth and dissemination in vitro and in vivo. GOLM1 was found to bind epidermal growth factor receptor (EGFR) and, in response to EGF, colocalized with the internalized receptor in Rab5-positive early endosomes, enhancing polarized redelivery of EGFR back to the plasma membrane in a Rab11-dependent manner, and promoting cell migration. Notably, an intact GOLM1-EGFR interaction and a completely functional GOLM1 were indispensable for EGFR recycling and downstream signaling. This study reveals an intracellular vesicle trafficking network responsible for sustaining metastasis in HCC. Because GOLM1 was also implicated in the recycling of c-MET and VEGFR, targeting GOLM1 may have broad therapeutic potential.

Ye QH, Zhu WW, Zhang JB, Qin Y, Lu M, Lin GL, et al. GOLM1 modulates EGFR/RTK cell-surface recycling to drive hepatocellular carcinoma metastasis. Cancer Cell 2016;30:444–58.

Xu and colleagues identified the cell adhesion molecule CD166 as highly expressed in multiple myeloma (MM) and primary bone marrow (BM) cells. CD166-positive cells homed to the BM of immunodeficient NSG mice better than CD166-negative mice. Silencing CD166 in MM cells led to longer survival, reduced tumor burden, and fewer osteolytic lesions compared with control MM mice. In ex vivo organ cultures, CD166 deficiency in MM or BM cells from MM patients had less bone resorption. Further, after intratibial engraftment, CD166 deficiency in MM cells caused reduction in osteolytic disease. CD166 inhibited BM-derived osteoblast progenitors via suppression of RUNX2. Conversely, CD166 expression in MM cells enhanced osteoclastogenesis by activating TRAP6-dependent signaling pathways in osteoclast progenitors. Thus, the authors have identified CD166 as pivotal to the homing of MM cells to the BM and MM progression.

Xu L, Mohammad KS, Wu H, Crean C, Poteat B, Cheng Y, et al. Cell adhesion molecule CD166 drives malignant progression and osteolytic disease in multiple myeloma. Cancer Research; Published OnlineFirst September 7, 2016; doi: 10.1158/0008-5472.CAN-16-0517.

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.