oss of neurofibromin 1 (NF1) leads to hyperactivation of RAS, which in turn signals through the RAF/MEK/ERK and phosphoinositide 3-kinase (PI3K)/mTOR pathways to regulate cell growth and survival. Because NF1-deficient acute myeloid leukemias are sensitive to MEK inhibitors, we investigated here whether NF1-deficient glioblastoma multiforme (GBM) would respond to MEK inhibition. In 19 GBM cell lines, we found that treatment with the clinically available MEK inhibitors PD0325901 or AZD6244 decreased levels of phospho-ERK, the downstream effector of MEK, regardless of NF1 status. However, growth inhibition occurred only in a subset of NF1-deficient cells, in association with decreased levels of cyclin D1, increased levels of p27, and G1 arrest. As a single agent, PD0325901 suppressed the growth of NF1-deficient, MEK inhibitor–sensitive cells in vivo as well. Mechanistically, NF1-deficient, MEK inhibitor–sensitive cells were dependent upon the RAF/MEK/ERK pathway for growth and did not activate the PI3K pathway as a mechanism of acquired resistance. Importantly, NF1-deficient cells intrinsically resistant to MEK inhibition were sensitized by the addition of the dual PI3K/mTOR inhibitor PI-103. Taken together, our findings indicate that a subset of NF1-deficient GBMs may respond to MEK inhibitors currently being tested in clinical trials. Cancer Res; 72(13); 3350–9. ©2012 AACR.
This paper provides a better understanding of the underlying apoptic pathways responsible for tumor cell lysis and possible new therapeutic targets.
Genomics has brought many important discoveries and changes into science and medicine. The central dogma of molecular biology where "DNA makes RNA and RNA makes protein" is well established (yet controversial). Watson and Crick had originally proposed a double stranded model of DNA. This served as a useful foundation for further understanding and research. Throughout the years more investigations demonstrated that human evolution was far more complex than originally believed. There was originally a great deal of migration around the world causing some hereditary lineages to become isolated and others to become more robust.
The life cycle of a cell usually begins with division and continues with replication. However, errors in mitosis can cause a cell to undergo apoptosis or form into a tumor. Differentiating between the two final pathways may be critical in helping to guide cells towards a less destructive pathway for the host organism. The critical component has to do with the environment the cell is in. The cell receives information from the outside environment and adapts according to received stimuli.
This project has been conceived to leverage a team based approach for elucidating the underlying apoptotic pathways responsible for tumor lysis and cell death. Combining the current understanding of molecular dynamics, genomics, and contrast imaging agents to discover novel therapeutic targets and further the current understanding of tumor biology within the genomic era.