By Kenneth Anderson, MD

2008-01-01

Dr. Anderson indicated no relevant conflicts of interest.

Stommel JM, Kimmelman AC, Ying H, et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science. 2007;318:287-90.

Therapies targeting receptor tyrosine kinases (RTKs) have provided remarkable responses in both hematologic cancers and solid tumors, but their clinical efficacy has been limited in many cases, and few, if any, patients are cured. In a recent seminal work that has identified obstacles to meaningful responses to single-agent therapies targeting RTKs, Stommel and colleagues have utilized a glioblastoma (GBM) model to examine coactivation of RTKs triggering downstream phophatidylinositol 3-kinase (PI3K) signaling in cell lines, xenotransplants, and primary patient tumor cells. Remarkably, using an antibody array to assess for phosphorylation of 45 RTKs, they found three or more activated RTKs in each tumor, and up to 10 activated RTKs in some cases. In elegant experiments to assess the biologic and clinical relevance of this upstream multiple RTK coactivation, they utilized combinations of RTK inhibitors and/or RNA interference to examine the effects on PI3K signaling, cell survival, and anchorage-independent GBM growth. Importantly, combinations of RTK inhibitors, but not single agents, inhibited PI3K signaling and these functional sequelae.

These studies have fundamental implications for our translational studies to treat cancer. First, in the laboratory, they suggest that individual patients’ tumor cells may need to be profiled in order to identify specific activated RTKs and then select cocktails of targeted therapies in order to achieve meaningful inhibition of cell signaling. Alternatively, it may be possible to choose a single agent targeting multiple RTKs selected for individual patients. A third possibility is to target downstream molecules in cell signaling cascades, thereby theoretically resulting in significant inhibition of relevant signaling pathways and sequelae, regardless of the number of upstream RTKs coactivated. Importantly, translation of these findings will inform the design of clinical trials to evaluate targeted therapies in patients most likely to respond, avoiding the development of drug resistance and allowing for fewer side effects.

The paradigm of combination therapies to cure childhood acute lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and testicular cancer is well established. Most importantly, the current study suggests that combinations of targeted therapies directed at activated RTKs, or single agents targeting multiple activated RTKs, may allow for more broad application of this paradigm of successful combination therapies in cancer.

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