Model Organisms in Drug Discovery

136 DROSOPHILA – A MODEL SYSTEM
be sufficient, even in a sensitized background. By screening large numbers of
mutagenized chromosomes to reach multiple saturation of the genome it is
possible to identify rare antimorphic (dominant-negative) mutations, which
results in a more than 50% reduction of functional gene product. In a screen
for dominant modifiers of an activated Raf kinase, Dickson et al. (1996) found
five alleles of hsp 83, the Drosophila homolog of hsp 90. All these mutations
are antimorphs (dominant-negative function) and show that the HSP90
protein plays an important role in modulating Raf activity. However, the
chance of identifying such antimorphic mutations is rare and unpredictable.
A more reliable method for identifying genes whose products perform
essential but not rate-limiting functions in a disease pathway is to screen
for recessive suppressors. This is achieved by combining the tissue-specific
recombination system (ey-FLP) with a genetically sensitized system. The
phenotype of homozygous mutant eye tissue is not analyzed in a wild-type
background but in a background of a hyperactivated signaling pathway
that causes a rough eye phenotype. We will take the WNT pathway as
example.
In many human cancers, the WNT pathway is constitutively active and, as a
result, cells receive a continuous signal to proliferate. In a Drosophila model,
ectopic activation of wg (encoding the Drosophila homolog of mammalian
Wnt proteins) in the compound eye leads to uncoordinated cell growth and
cell death, resulting in readily detectable small, rough eyes, which resembles
the behavior of cancer cells. We performed a screen for recessive mutations
that modifies the rough eye (C. S. and K. Basler, unpublished results). The
screen is based on the ey-Flp/FRT technique, which induces homozygous
mutant clones in the head (see earlier section on screens for recessive
mutations). Blocking a critical downstream component of ectopic Wg
transmission will suppress the dominant eye phenotype caused by sev-wg.
The power of this screen is its stringency for Wg interacting genes and the
possibility of identifying partially redundant genes whose products only
become limiting in cells in which the WNT pathway is hyperactivated.
Importantly, gene products identified in this way must not be essential for
normal WNT signaling during development. Because if they were, the cells
lacking this component owing to a homozygous mutation in the corresponding
gene will not develop and contribute to the eye structure. In other
words, this type of screen will only identify genes whose products are essential
for abnormal WNT signaling but not for normal WNT signaling. From a
purely functional point of view, these are the ideal drug targets. Inhibiting
their function with a drug may block overactive WNT signaling in the cancer
cell but will not interfere with normal WNT activity in other cells.
Whether such genes exist and whether they encode drugable proteins will be
apparent when the first candidates from this screen have been characterized
molecularly.