Yoshida et al. Page 2919

The epidermal growth factor receptor (EGFR) is activated through corresponding gene amplification, and/or mutation in approximately 40% of glioblastomas, and the large subgroup of glioblastoma patients whose tumors have this molecular characteristic are thought to be excellent candidates for benefitting from EGFR-targeted therapy. However, available EGFR inhibitors have shown poor activity in treating glioblastoma patients, in large part due to poor CNS penetration. In this report, Yoshida and colleagues show that NT113, a novel pan-ERBB inhibitor, has excellent CNS penetration and activity against glioblastoma xenografts with activated EGFR, thereby supporting the clinical development of NT113 for treating this cancer.

Smyth et al. Page 2793

Clinical resistance to BRAF and MEK inhibitors demonstrates the need for further drug combination approaches in melanoma. The use of AT13387, an HSP90 inhibitor currently in clinical trials, to tackle resistance was investigated. AT13387 was effective in melanoma models with acquired resistance to BRAF and MEK inhibitors, and also delayed the emergence of resistance when combined upfront with vemurafenib in sensitive models. These data suggest HSP90 inhibition could be used to combat clinical resistance to BRAF and MEK inhibitors in melanoma. Significantly, frontline combinations could delay the emergence of resistance and extend progression-free survival, supporting clinical investigation in BRAF-mutant melanoma.

Bola et al. Page 2805

Effective lactate transport is crucial for tumor cell homeostasis. AZD3965 inhibits the function of the lactate transporter MCT1, and in small cell lung cancer cells (SCLC) treatment with AZD3965 causes an increase in glycolysis via inhibition of lactate uptake. The treatment of SCLC xenografts with a combination of AZD3965 and fractionated radiation resulted in a significantly greater therapeutic effect than the use of either modality alone. These data support the notion of combining MCT1 inhibition with radiotherapy in the treatment of SCLC and other solid tumors.

Ganesan et al. Page 3175

Triple-negative breast cancer (TNBC) patients have poor treatment outcomes and there are no validated targets for therapy. Of the 106 patients with metastatic TNBC treated in our phase I clinic, patients treated on matched therapies had higher response rates, and improved progression-free survival (PFS) than patients on nonmatched therapies. Patients on combinations of chemotherapy and targeted agents had improved PFS compared with those on either chemotherapy or targeted therapy alone. In particular, combinations that included chemotherapy with antiangiogenic therapy and/or PI3K/AKT/mTOR pathway inhibitors showed improved PFS. Currently, next-generation sequencing in a large prospective study is ongoing.