Genome-Based Classification of Lung Cancer
Seidel and colleagues asked whether genomic analyses could augment pathologic classification for adenocarcinoma, squamous carcinoma, small-cell lung carcinoma, and large-cell carcinoma. As expected, adenocarcinomas were enriched for KRAS and EGFR mutations, small-cell lung cancers for MYCN, and squamous carcinomas for NFE2L2. Large-cell carcinoma tumors showed alterations typical of all the other subtypes, enabling reclassification. An algorithm applied to 5,145 tumors provided a genome-based diagnosis in 75% of cases. Importantly, the incorporation of genomic alterations led to an improvement in patient outcome due to the identification of EGFR-mutant and ALK-rearranged cancers, both of which were amenable to effective targeted therapy. These findings support an integrated histologic-genomic approach to the classification of lung cancer.
Role of AKT3 in Triple-Negative Breast Cancer
Chin YR, Yoshida T, Marusyk A, Beck AH, Polyak K, Toker A. Targeting akt3 signaling in triple negative breast cancer. Cancer Res; Published OnlineFirst December 12, 2013; doi:10.1158/0008-5472.CAN-13-2175.
Using a short hairpin RNA screen to identify kinases frequently amplified and overexpressed in breast cancer, Chin and colleagues demonstrated that AKT3 kinase was required for growth in triple-negative breast cancers (TNBC). Silencing AKT3 in TNBC cells inhibited cell growth in vitro and in vivo, with dramatic inhibition in three-dimensional spheroid and xenograft growth (mediated by the cell-cycle inhibitor p27). Growth, migration, and invasion were selectively affected by AKT3, as compared with AKT1 or AKT2. Moreover, silencing AKT3 expression in TNBCs sensitized cells to a pan-AKT inhibitor. This study shows that AKT3 plays a significant role in TNBCs and might serve as a therapeutic target, increasing treatment options for patients.
New Genetically Engineered Model for Ovarian Carcinoma
Perets R, Wyant G A, Muto KW, Bijron JG, Poole BB, Chin KT, et al. Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models. Cancer Cell 2013;24:751–65.
Perets and colleagues describe a new mouse model of high-grade serous ovarian cancer (HGSC). Pax8, essential for development of fallopian tubes but not ovaries, that was used as a tissue-specific driver targeting Brca, Trp53, and Pten deletions in fallopian tube secretory cells. The mice developed serous tubal epithelial carcinomas that spread to the ovary and peritoneum, recapitulating human disease. The lesions expressed key tumor and serum proteins used clinically in patients with HGSC. Genomic analysis revealed alterations that were similar to those in human HGSC tumors. This new model not only provides insights into the origin and pathogenesis of HGSC but also will be valuable in testing therapies and methods for early detection in women at risk.
A Novel EGFR Inhibitor with Mutant Selectivity and Wild-type Sparing Properties
Walter AO, Sjin RTT, Haringsma HJ, Ohashi K, Sun J, Lee K, et al. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M mediated resistance in NSCLC. Cancer Discov 2013;3:1404–15.
Lung cancer patients treated with inhibitors of EGFR often develop resistance due to gatekeeper mutations (T790). Walter and colleagues developed CO-1686 (orange), which covalently binds C797 in the EGFR-kinase domain (green). C0-1686 showed 22-fold selectivity for inhibiting EGFRT790M over EGFRWT, selectively blocking proliferation, EGFR phosphorylation, and mouse models of lung cancer driven by EGFRT790M. CO-1686-resistant clones showed reduced dependence on EGFR for viability, and enrichment of genes driving epithelial–mesenchymal transition. CO-1686-resistant clones upregulated pAKT, and CO-1686 synergized with AKT inhibition in these clones. CO-1686 is in an early phase of clinical testing and shows promise for improved efficacy in patients with EGFRT790M-resistant mutations and reduced toxicity due to relative sparing of EGFRWT.
Taking a Notch out of Wnt-Driven Cancers
Liu and colleagues identified a novel Wnt inhibitor, LGK974. LGK974 inhibited secretion of Wnt by attenuating palmitoylation via binding and inhibiting the O-acyltransferase Porcupine (PORCN). LGK974 inhibited Wnt-driven xenografts with good association among pharmacokinetics, efficacy, and decreased expression of Wnt biomarkers. Sustained pathway inhibition was not required for efficacy in vivo, perhaps explaining a favorable therapeutic index. Exome sequencing of LGK974-responsive head and neck squamous cell carcinoma cell lines revealed frequent loss-of-function mutations in NOTCH1, with expression of Notch inhibiting growth. Thus, in addition to describing a novel small-molecule Wnt inhibitor, this article describes a biomarker to identify patients most likely to benefit from clinical use of this inhibitor.
Radiation and T-cell Immunotherapy
Klug F, Prakash H, Huber PE, Seibel T, Bender N, Halama N, et al. Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 2013;24:589–602.
Using models for melanoma and pancreatic islet cell tumors, Klug and colleagues found that low-dose irradiation promoted infiltration by T cells as well as normalization of the vasculature, with antitumor response in an adoptive T-cell transfer model. Low-dose irradiation promoted proliferation and differentiation of macrophages into M1-like iNOS (NOS2)-expressing macrophages that orchestrated CTL recruitment, killing tumor cells by inducing endothelial activation and TH1 chemokines, while suppressing angiogenic, immunosuppressive, and tumor growth factors. These results were reproduced in samples from a clinical trial in pancreatic cancer. Larger studies are needed to confirm these results, which suggest low-dose irradiation as a means to enhance local antitumor immunity in pancreatic cancer.
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.