Inhibitors of Pathways Downstream of KIT & PDGFR
Drugs in this category inhibit targets that are "downstream" of KIT and PDGFRA, meaning that these targets are activated as a result of prior activation of KIT or PDGFRA. Some of these drug targets are shown in the following figure.
Figure: Simplified schematic of KIT signal transduction. Physiologic KIT activation is triggered by binding of the dimeric KIT ligand stem cell factor (SCF) leading to homodimerization of two KIT molecules. This is accompanied by structural changes in the receptor resulting in activation of the KIT kinase domain. Phosphorylated tyrosine residues on KIT serve as binding sites for various cell signaling proteins. These proteins include members of the PI3-K/AKT, RAS/RAF/MAPK and the JAK/STAT pathways. Ultimately, the phosphorylated KIT receptor stimulates intracellular signaling pathways controlling cell proliferation, adhesion, apoptosis, survival and differentiation. (Figure graciously provided by Anette Duensing, M.D.)
- everolimus (RAD001)
- sirolimus (Rapamune) currently in combination trials, FDA-approved
- temsirolimus (Torisel)
- deforolimus AP23573
- XL765 (also inhibits mTOR)
- GDC-0941 bismesylate
- GDC-0980 (also inhibits mTOR)
The PI3K pathway (which includes other important kinases called AKT and mTOR) is immediately downstream from KIT and other cell surface receptors. Also known as the "survival kinase pathway," PI3K appears to be a major signaling protein in GIST, promoting cell survival and blocking cell death. Inhibiting PI3K with a drug might be an effective way to stop GIST.
An inhibitor of PI3K might circumvent Gleevec resistant GIST tumors when Gleevec resistance results from a heterogenous mix of secondary mutations within the KIT gene, which would be difficult to treat by a single agent KIT inhibitor.
Furthermore, many different cell surface receptors stimulate the PI3K pathway. Thus, inhibiting PI3K might be a way to stop GISTs that are driven by an unknown cell surface receptor (consider "wild type GIST") or else a G coupled receptor serving as part of hormonal signaling (consider pediatric GIST which might have a female hormonal aspect).
KIT stimulates additional downstream pathways besides the PI3K pathway (such as the MAPK-, JAK STAT-, and the Phospholipase C pathways, which support cell growth and division), and so it is unclear at the present if stopping PI3K alone would be as effective as stopping KIT itself.
The PI3K pathway is one of the most frequently mutated in human cancer. Now there are drugs coming into the clinical trial pipeline that block PI3K. Blocking PI3K however may potentially carry some toxicitiy issues such as drug-induced diabetes or weakening of the heart.
For a free-access medical paper about this drug strategy, see "Practicalities of Drugging the Phosphatidylinositol-3-Kinase/Akt Cell Survival Signaling Pathway"