Model Organisms in Drug Discovery

122 DROSOPHILA – A MODEL SYSTEM
carcinogenesis in humans and embryogenesis in Drosophila seem to be very
distinct processes, they both rely on cell communication via the WNT
pathway (Peifer and Polakis, 2000). The first Wnt gene, mouse Wnt-1, was
discovered nearly 20 years ago as a proto-oncogene. Furthermore, identification
of the tumor suppressor APC (adenomatous polyposis coli) has linked
colon cancer to WNT signaling. Tumor suppressor APC is a negative
regulator of the WNT pathway and is mutated in most colorectal tumors. It is
thought that inactivation of both APC alleles is one of the first steps occurring
in tumorigenesis (Polakis, 2000).
Around 5% of the Western population develop colorectal malignancies
during their lifetime. This not only leads to high medical costs but also to
premature death. In over 85% of all human colon cancers, but also in some
other cancers, the WNT pathway is aberrantly active and, as a result, the cells
receive a continuous signal to proliferate (Morin, 1999; Bienz and Clevers,
2000; Polakis, 2000). Given the high frequency and severity of colon cancer
and the fact that no good drug targets with enzymatic function have been
identified so far, research in this field has high priority. Because the WNT
pathway is highly conserved in flies and mammals, Drosophila can serve as an
excellent model system.
Our current view of the Wg signal transduction pathway is largely based on
genetic dissection of the pathway in Drosophila (Moon et al., 2002). The
secreted Wg protein acts via its receptor Fz (frizzled) and a short cascade of
downstream components to stabilize armadillo (Arm), the Drosophila
homolog of b-catenin, which together with pangolin/TCF (Pan/TCF)
activates transcription of Wg-responsive genes (Figure 5.1). In the absence
of a Wg signal, free cytoplasmic Arm/b-catenin is destabilized by the
negatively acting multiprotein complex containing APC, axin and glycogen
synthase kinase 3b (GSK3) (Cohen and Frame, 2001).
In the past, several genetic approaches to identify components of the Wg
pathway have been taken in Drosophila by a number of groups, including that
of K. Basler, a co-founder of The Genetics Company, Inc. We will describe
two of these. First, screens for recessive lethal mutations identified essential
components (i.e. arm) that caused a segment polarity phenotype similar to the
loss of Wg function (Nu¨sslein and Wieschaus, 1980). Second, screens for
suppressors of ectopic Wg signaling identified rate-limiting components in this
pathway (Brunner et al., 1997). In cancer cells the Wnt pathway is
constitutively active, due to either the loss of the tumor suppressor gene
APC or to activating mutations in b-catenin (Polakis, 2000). Drugs that
interfere with positively acting components of the WNT pathway at the end of
the cascade are thus attractive because such a block would disrupt the WNT
transduction pathway irrespective of the nature of the original defects leading
to WNT activation in various types of cancer cells. Ectopic WNT activation,
as it occurs in cancer cells, was mimicked in Drosophila by overactivating the