Biomedical Engineering Reference
In-Depth Information
[144]. siRNA synthetic lethal screens demonstrated that members of
this gene signature may not only have predictive value, but functional
relevance to enhance imatinib activity.
In other studies Belinsky and colleagues have shown that not all
GISTs that lack mutations in
, the so-called “wild-type”
tumors, are alike. Using whole-genome SNP-arrays they were able
to obtain high-resolution maps of the GIST's genome, both tumors
lacking
KIT
or
PDGFRA
mutations as well as mutant GISTs. Importantly,
these studies found that the majority of
KIT/PDGFRA
mutation-
negative, both pediatric and adult GISTs which are clinically more
resistant to imatinib-based therapies, generally do not possess the
large-scale chromosomal aberrations that are commonly found in
mutant GISTs [19, 80]. Based on these molecular studies, tumors
can be stratified into three groups:
KIT/PDGRFA
KIT/PDGFRA
mutation negative/
genome stable GISTs, and
KIT/PDGFRA
mutation positive/genome
mutation negative/genome instable
GISTs (Fig. 9.4). Furthermore, these
instable GISTs, and
KIT/PDGFRA
mutation negative/
genome stable GISTs were shown to greatly overexpress the insulin-
like growth factor receptor-1 (IGF1R) relative to other GISTs. Tarn
et al.
KIT/PDGFRA
demonstrated that IGF1R may be an interesting therapeutic
target to consider in GIST patients, especially in pediatric and adult
KIT/PDGFRA
mutation negative cases in which treatment options are
extremely limited.
mutation negative GISTs were shown
to greatly overexpress IGF1R (both at the protein and mRNA levels)
(Fig. 9.6) [75, 80, 145] and drugs that target IGF1R can inhibit the
ability of GIST cells to grow [75]. Clinical trials are being developed
to explore IGF1R as a target based on these and other molecular
studies. Finally, a proportion of the previous classified “wild-type”
GISTs that demonstrate genome instability have been shown to carry
mutations in the
KIT/PDGFRA
gene [19]. There are now several additional
reports indicating that the
BRAF
BRAF
gene is mutated in ~4-13% of
GISTs without
KIT
or
PDGFRA
mutations (e.g., [18]).
However, the
genetic changes in GISTs without
mutations is
not known, so we and others are currently using modern day deep
sequencing approaches to further explore the GIST genome in these
patients to uncover additional clues to help uncover the etiology
and define effective therapies. These are a few examples of how
work at the bench can be translated into a better understanding
of the disease and suggest ways to improve therapeutic modalities
influencing how patients will be treated at their bedside.
KIT/PDGFRA/BRAF
