De Cesare et al. Page 995

The epidermal growth factor receptor (EGFR) is a validated therapeutic target in many human cancers. In spite of the frequent EGFR overexpression in squamous cell carcinoma (SCC), the anti-EGFR antibody, cetuximab, as a single agent exhibits marginal efficacy. Our study shows an impressive efficacy of cetuximab/namitecan combination, which reflects a complete abrogation of EGFR expression, in SCC preclinical models characterized by high EGFR gene copy number. The study provides a molecular basis for a rational combination to be exploited for possible therapeutic applications in the clinical setting and suggests EGFR gene copy number as a possible marker for patient selection.

Gramatges et al. Page 904

Shortened constitutional telomere length is a well-established risk factor for the development of primary malignancies, related to genomic instability that may result from excessive telomere shortening. However, the relationship between telomere length and risk for second malignancies has not been explored. Gramatges and colleagues performed a matched case-control analysis of telomere length between survivors with and without second malignancies within the Childhood Cancer Survivor Study. A relationship was observed with shortened telomeres, driven by a highly significant association with thyroid second cancers. These results suggest cancer predisposition related to genetic or therapy-related telomere shortening, or other factors affecting telomere homeostasis.

Shiota et al. Page 951

Both protein kinase C (PKC) and Twist1 play an important role in cancer pathology, including epithelial-mesenchymal transition as well as treatment resistance. Shiota and colleagues have explored the signaling pathway evoked by androgen-deprivation therapy (ADT) for prostate cancer. ADT induced PKC activation and Twist1 induction. On the other hand, an inhibition of PKC, especially PKCβ and PKCϵ, suppressed Twist1 expression, indicating the novel relationship between PKC and Twist1. Accordingly, PKC inhibition combined with ADT such as novel antiandrogen enzalutamide exerted excellent synergistic anticancer effects, suggesting that PKC inhibition as an alternative of Twist1 inhibition might be a promising therapeutic strategy.

Nies et al. Page 985

The uptake transporter SLC22A1 (OCT1) has been suggested to contribute to imatinib resistance; however, its role for imatinib transport into cells is controversial. Nies and colleagues applied an array of in vitro and in vivo model systems to systematically elucidate the contribution of OCT1 to imatinib transport. Using various OCT1-overexpressing cells, leukemic cells being devoid of OCT1 mRNA and protein, and Oct1-deficient mice the authors demonstrate that cellular uptake of imatinib is independent of OCT1. Therefore, OCT1 is apparently not a valid biomarker for imatinib resistance.