Ross et al. Page 2668

Next-generation sequencing (NGS) can be applied to routine formalin-fixed paraffin-embedded clinical samples as a means to further classify the lobular phenotype of invasive breast cancer into tumors with and without E-cadherin (CDH1) mutations. When Ross and colleagues used this approach to evaluate invasive lobular carcinoma (ILC) with CDH1 mutation, they found a significant enrichment of genomic alterations in the targetable HER2 (ERBB2) gene. Of the 22 CDH1-mutated ILCs evaluated in this study, 6 (27%) featured ERBB2 alterations, only 1 of which was a classic gene amplification that was detectable by the routine slide-based ERBB2/HER2 tests in common practice (immunohistochemistry and FISH). The 5 gene amplification-negative ERBB2 alterations detected included 4 base substitutions (mutations) and 1 novel ERBB2-GRB7 gene fusion. Recent evidence suggests that ERBB2 mutations may be sensitive to standard anti-HER2 targeted therapies in breast and other cancers. Thus, given the relatively high incidence of treatable ERBB2 alterations in relapsed and metastatic CDH1-mutated ILC, the use of NGS to identify these alterations which cannot be detected by routine slide-based tests has the potential to change routine clinical practice.

Coffee et al. Page 2688

Treatment of patients with BRAFV600E colorectal cancer is a critical unmet medical need. To address this deficiency, Coffee and colleagues have developed a novel genetically engineered mouse model for BRAFV600E colorectal cancer. Their results suggest that BRAFV600E tumors are not sensitive to single-agent BRAF inhibition and implicate concurrent signaling through the parallel phosphoinositide 3-kinase (PI3K)/mTOR signaling axis. Using a combination of in vitro and in vivo approaches, the authors show that simultaneous targeting with both a BRAF inhibitor and a PI3K/mTOR inhibitor may be required for successful treatment in this population of colorectal cancer patients.

Varsano et al. Page 2710

Targeting “undruggable targets,” such as transcription factors, is a challenge. Varsano and colleagues address this task by focusing on altering the transcription factor's subcellular localization. Based on their findings that subcellular localization dictates ATF2 oncogenic (nuclear) or tumor-suppressive (cytosolic) function, they developed a high-content screen and used it to identify small molecules that promote ATF2 nuclear export. The hits identified were shown to sensitize melanoma to cell death along the protein kinase C signaling pathway, which drives ATF2 nuclear localization and oncogenic activity in these tumors. The proof-of-concept screen reported in this study provides the foundation for larger screening campaigns as well as further development and characterization of the small molecules that were identified.

Jimeno et al. Page 2766

Jimeno and colleagues evaluated the Smoothened receptor inhibitor IPI-926 in advanced cancer patients with a focus on basal cell carcinoma of the skin. The uniqueness of this phase I trial is that IPI-926 is a direct derivative of cyclopamine, the plant alkaloid whose discovery enhanced our understanding of the hedgehog pathway (HhP). The HhP is dysregulated in a variety of solid tumors and is proposed to provide key growth and survival signals to tumor cells. IPI-926 was administered with a tolerable toxicity profile in patients with advanced solid tumors and has shown substantial efficacy in patients with basal cell carcinoma.