Horizontal and Vertical Signal Pathway Inhibition
July 20, 2010 5 Comments
The importance of signal pathway inhibition in human tumor primary culture microspheroids.
Signal transduction pathways are important targets in cancer therapy. Small molecule inhibitors for the tyrosine kinase and serine threonine kinase pathways are already available for clinical therapy. Additionally, compounds targeting the PI3K, AKT and MEK pathways will be available in the coming years. To explore the interaction of these parallel survival pathways, we compared activity and combined these inhibitors in human tissues — the results were instructive.
Our findings include favorable interactions between EGFr tyrosine kinase inhibitors and compounds that block the PI3K pathways. The most active combinations were those that inhibited the cross-talk between pathways (horizontal inhibition) over drug combinations that targeted the same pathway at different downstream points (vertical inhibition). Similar observations have been made combining PI3k inhibitors and MEK inhibitors. One such report in PNAS (May 10, 2010) closely paralleled the work conducted in our laboratory, Rational Therapeutics, that we reported at the AACR.
Noteworthy, a series of studies utilizing these combinations, indicate that certain tumors respond to their drug exposure by undergoing autophagic death, not necrotic or apoptotic. This distinction is possible, as the Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD®) platform has the capacity to measure all forms of cell death – apoptotic and non-apoptotic.
We continue these studies in numerous solid tumors to explore those diseases that will be the best candidates for these types of combination therapies. Please leave a comment below if you would like more information on these studies.