Biology Reference
In-Depth Information
B. Future Directions
A limited number of well-studied synthetic lethal interactions have been
identified in cancer cells. These findings give hope for the translation of
successful basic research into improvements in the clinical treatment of can-
cers. Unbiased screening approaches will be necessary to discover new syn-
thetic lethal combinations. High-throughput technologies such as genome-
wide RNAi approaches or screening of chemical compound libraries should
enable us to explore the promising concept of synthetic lethality in greater
detail. New sequencing techniques allow gathering of more information about
mutations in cancer cell lines and primary tumor samples.
Many ongoing studies discussed earlier focus on the loss of function in
tumor suppressor genes such as BRCA or p53 deficiency. However, there is
great potential for the discovery of lethal interactions with other genetic
lesions, for example, gain-of-function mutations as described for p53.
142
Mutations in
p53
can lead to elevated activation of the Rho-pathway and
thereby increase proliferation and evasion potential in tumor cells.
143,144
Just
as for loss-of-function mutations, this gain of novel properties specific to cancer
cells could offer alternative possibilities for p53-targeted approaches. In addi-
tion, the principles of synthetic lethality can be applied for common ''non-
druggable'' oncogenes, such as
Myc
amplifications or
K-ras
mutations, some of
the most commonly mutated oncogenes. Recent RNAi screens for synthetic
lethal interactors with oncogenic Ras found that
K-ras
mutated tumor cells are
hypersensitive to the loss of polo-like kinase 1 (Plk1) and STK33,
145,146
which
could be potentially druggable targets.
Synthetic lethality has emerged as an important concept to understand the
function of genes, and the interdependence between pathways following rewir-
ing of signaling networks in tumor cells. It forms the basis for new strategies in
targeted anticancer therapy that focus on the oncogenic context of cancer cells
and make use of unique tumor properties that are not shared by normal tissue.
Currently, many of these novel approaches exploiting synthetic lethal genes
are highly effective in preclinical studies, some holding great promise for a
successful validation in the clinic.
References
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cancer susceptibility syndromes.
J Clin Oncol
2006;
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2. Kastan MB, Bartek J. Cell-cycle checkpoints and cancer.
Nature
2004;
24
:316-23.
3. Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy: oncogene and non-oncogene
addiction.
Cell
2009;
432
:823-37.
4. Hanahan D, Weinberg RA. The hallmarks of cancer.
Cell
2000;
136
:57-70.
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