Biology Reference
In-Depth Information
Exploiting Synthetic Lethal
Interactions Between DNA
Damage Signaling,
Checkpoint Control, and p53
for Targeted Cancer Therapy
Sandra Morandell and
Michael B. Yaffe
Departments of Biology and Biological
Engineering, David H. Koch Institute for
Integrative Cancer Research, Massachusetts
Institute of Technology, Cambridge,
Massachusetts, USA
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
290
A. Targeting Cancer Genes in the Context of DNA Damage . . . . . . . . . . . . . . . . . . .
290
B. The DNA Damage Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
291
II. The Concept of Synthetic Lethality in Cancer Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . .
295
III. Synthetic Lethality Between PARP1 and BRCA1/2 as a Model for Enhancing
DNA Damage-Induced Cell Death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
295
IV. Synthetic Lethality in the Context of p53 Mutations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
297
A. Synthetic Lethality Between p53 and the ATR/Chk1 Signaling Pathway .
297
B. Synthetic Lethality Between p53 and ATM/Chk2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
300
C. Sensitizing Chemo-Resistant Tumors that Have p53 Function:
A Role for DNA-PKcs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
302
D. Synthetic Lethality Between p53 and MK2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
303
V. Potential for Future Therapies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
305
A. Novel Players in the Genotoxic Stress Response: Posttranscriptional
Regulation of Selective mRNAs Upon DNA Damage . . . . . . . . . . . . . . . . . . . . . . . .
305
B. Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
307
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
307
DNA damage signaling and checkpoint control pathways are among the most
commonly mutated networks in human tumors. Emerging data suggest that
synthetic lethal interactions between mutated oncogenes or tumor suppressor
genes with molecules involved in the DNA damage response and DNA repair
pathways can be therapeutically exploited to preferentially kill cancer cells.
In this review, we discuss the concept of synthetic lethality with a focus on
p53
,
a commonly lost tumor suppressor gene, in the context of DNA damage
signaling. We describe several recent examples in which this concept was
successfully applied to target tumor cells in culture or in mouse models, as
well as in human cancer patients.
