Highlights of This Issue

Abstract

ALK-rearrangement–positive lung cancers are sensitive to ALK inhibitors. However, the magnitude and duration of response are heterogeneous. By making use of the Ba/F3 cell line model, Heuckmann and colleagues demonstrate that different EML4-ALK variants show differential sensitivity to ALK inhibitors. Furthermore, a combination of ALK and HSP90 inhibitors led to synergistic cytotoxicity in EML4-ALK–expressing cells. Consequently, these results might explain some of the heterogeneous responses observed in the clinic and suggest that the application of ALK and HSP90 inhibitors should take into account the precise variant of ALK fusion to enhance tumor control.To identify the potential therapeutic kinase targets in osteosarcoma cells, Duan and colleagues performed a comprehensive kinome-wide screening. Their results show that knocked down CDK11 expression inhibits tumor cell growth and induces apoptosis. High CDK11 expression levels in osteosarcoma patients were associated with significantly shorter survival than were low levels of CDK11 expression in osteosarcoma patients. Systemic in vivo administration of siRNA of CDK11 reduced the tumor growth. These observations demonstrate that CDK11 signaling is essential in osteosarcoma cell growth and survival. CDK11 may be a promising therapeutic target in the management of osteosarcoma.Stem cell signaling has been associated with the worst overall survival in patients with malignant pleural mesothelioma (MPM), a cancer associated with tissue damage due to asbestos. Shi and colleagues analyzed the expression of hedgehog signaling components in tumors and in primary cultures maintained in serum-free conditions at 3% oxygen. Increased levels of hedgehog transducer GLI1 were observed in tumors compared with nontumoral tissue, and inhibitors of the hedgehog pathway reduced cell growth by a mechanism involving decreased expression of YAP, a transcription factor controlling survivin. This mechanism is particularly important because MPM “driver mutations” include disruption of NF2 signaling, which keeps YAP under control.Studies conducted by Cohen and colleagues serve to illustrate the feasibility of administering weekly oral sirolimus to patients with advanced cancer. Moreover, these studies show that the bioavailability of sirolimus could be significantly enhanced by simple coadministration of CYP3A inhibitors, a principle that could be applied to many antineoplastic agents that would lead to tremendous cost savings. Finally, the results from these studies clearly indicate that sirolimus should be studied further as a lower-cost alternative to existing on-patent mTOR inhibitors.