John et al.Page 5636

The presence of an immunosuppressive microenvironment induced by tumors and host regulatory cells can limit the full potential of adoptive T-cell immunotherapy. John and colleagues demonstrated that specifically blocking PD-1 immunosuppression can potently enhance tumor eradication in mice following adoptive transfer of CAR T cells in the absence of pathology. Therapeutic responses were strongly correlated with increased CAR T-cell function and a concomitant decrease in MDSC's at the tumor site. These results are likely to increase the effectiveness of immunotherapy against a number of cancers that are currently resistant to first-line treatment.

Yepuru et al.Page 5613

Although steroidogenic enzyme AKR1C3 is consistently upregulated in castration-resistant prostate cancer (CRPC). Its role, if any, in progression to castration resistance is unknown. Yepuru and colleagues demonstrate that AKR1C3 not only contributes to this recognized role as a steroidogenic enzyme but also plays a dual role as an AR-selective coactivator. While overexpression of AKR1C3 increases androgen-dependent prostate cancer and CRPC growth, inhibition of AKR1C3 reduces CRPC growth. These effects were mediated by both its enzyme and coactivator functions. The findings depict, for the first time, a functional role for AKR1C3 and propose AKR1C3 as pharmacologically targetable AR-selective coactivator.

Wu et al.Page 5699

The MET pathway is frequently activated in human cancer and is implicated as a resistance mechanism to targeted therapeutics. Wu and colleagues demonstrated that treatment with LY2801653, a novel oncokinase inhibitor with MET as one of its targets, inhibited tumor growth in non–small-cell lung cancer cell line and patient tumor-derived xenograft mouse models. In the MET-dependent orthotopic model (NCI-H441), LY2801653 treatment inhibited both primary tumor growth and metastasis, and prolonged survival of tumor-bearing animals. Mechanistic studies demonstrated that LY2801653 inhibited MET-pathway signaling, anchorage-independent growth, migration, and invasion. These results support the ongoing clinical development of LY2801653 and suggest that differences in the MET activation status of tumors may be predictive of response.

Baker et al.Page 5758

A mechanism of resistance to FLT3 inhibitors in patients with FLT3-ITD-positive AML is the acquisition of secondary FLT3 tyrosine kinase domain (KD) mutations. To explore the evolution of KD mutations during tyrosine kinase inhibitor (TKI) therapy, Baker and colleagues performed deep amplicon sequencing of FLT3 in leukemic blast samples from patients during treatment with sorafenib and sunitinib. KD mutations at residues D835 and F691 could be detected early after commencement of therapy in morphologic remission samples, and subsequently monitored in response to individual TKIs. Application of sensitive sequencing methods during therapy may allow individualized treatment with currently available FLT3 inhibitors.