Chatterjee et al. Page 793

Although the use of Hsp90 inhibitors had emerged as a promising therapeutic approach for the “undruggable” KRAS, these agents failed in the clinic due to the development of rapid resistance. Chatterjee and colleagues set out to understand the mechanism(s) of acquired resistance to the Hsp90 inhibitor ganetespib, in order to develop rational Hsp90 inhibitor combinations to test in KRAS mutant NSCLC. They identified p90RSK as a critical targetable node in the ganetespib resistance mechanism and provided the preclinical rationale for the use of novel Hsp90 inhibitor combinations with ERK or PI3K/mTOR inhibitors that can be tested in the clinic.

Liu et al. Page 775

Hairy and Enhancer-of-split related with YRPW motif (Hey) transcription factors are highly expressed in a variety of cancers. However, few articles cover the important roles of Hey in tumor progression and avenues for cancer therapy through targeting Hey factors. Here, Liu and his colleagues discussed the mechanisms governing Hey factors in tumorigenesis, outlined successful agents reversing Hey expression and provided strategies to target Hey directly. Hey factors-targeted therapeutics may provide promising approaches for cancer treatment and help to improve clinical outcomes.

Burova et al. Page 861

Antibodies blocking the PD-1/PD-L1 interaction have been shown to enhance anti-tumor immunity in patients with diverse cancers. This report describes the preclinical characterization of REGN2810, a novel, fully human high-affinity anti-PD-1 antibody. REGN2810 enhances human primary T cell responses in vitro, and inhibits the growth of syngeneic tumors in mice genetically engineered to express a chimeric human/mouse PD-1 receptor from the mouse locus. PD-1 humanized mice allow for the first time to evaluate in vivo the preclinical activity of a clinical PD-1 blocking antibody. These preclinical results validate REGN2810 as a promising candidate for cancer immunotherapy.

Husain et al. Page 948

Collection of cell-free DNA (cfDNA) from the blood of individuals with cancer has permitted noninvasive tumor genome analysis. Detection and characterization of cfDNA in ascites and pleural effusions have not yet been reported. Husain and colleagues analyzed cfDNA in effusions from individuals with metastatic cancer and discovered copy number variations and somatic mutations within the effusate. The results indicate that cfDNA from ascites and pleural effusions may provide additional information complementing tumor and plasma cell-free DNA molecular characterization, and a context for important insights into clonal dynamic change within primary tumor and metastatic deposits.