Stommel, J.M., Kimmelman, A.C., Ying, J., Nabioullin, R. et al. Coactivation of Receptor Tyrosine Kinases Affects the Response of Tumor Cells to Targeted Therapies. Science, 318, 287-290 (October 12, 2007).
Working under the hypothesis that a combination of receptor tyrosine kinases (RTKs) are responsible for the survival and growth of some types of cancer, a consortium of scientists investigated the effect of RTK inhibitors, alone and in combination, on glioblastoma multiforme (GBM) cells in culture.
This type of tumor is particularly virulent, resulting in death in about 12 months from diagnosis, and RTKs occupy a crucial step in the phosphinositide 3-kinase (PI3K) tumor progression pathway. An assessment of 20 different GBM cell lines identified 19 in which three or more activated RTKs could be detected. This coactivation rendered cultured cells resistant to single RTK inhibitors, based upon PI3K association with GAB1, a complex that forms downstream from RTK activation. Yet, treatment with two inhibitors (to epidermal growth factor receptor and to MET) significantly reduced downstream signaling and culture viability. The use of three inhibitors with a different GBM cell line resulted in an even more dramatic inhibition of cell viability and culture growth.
The clinical relevance of these findings was supported by the observation that 14 primary human GBM tumors contained multiple activated RTKs, though they were not detectable in normal brain tissue. Moreover, individual cells coexpressed activated RTKs, thereby supporting the hypothesis that early redundancy in PI3K pathway renders cancer cells refractory to single-agent inhibition.
The results suggest that multiple inhibitors are needed for effective anticancer activity targeting RTKs. Indeed, it may be possible to quickly evaluate activated RTKs in a patient’s tumor to prepare an optimal combination therapy.
Message posted by: Keith Markey
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