5.1.2. to match synthetic lethal associations and

5.1.2. Synthetic lethality, a revolution in
the era of personalized treatment

lethality can be used to take advantage of cancer cells’ dependence on a DNA
repair pathway by inhibiting another unrelated pathway, which in turn causes
cell death (20). Novel small molecules in
pre-clinical and clinical trials combined with individual aberrations in tumors
are the focus of cancer treatment today, because this combination should only
lead to tumor killing sparing normal cells from toxicity (21). Synthetic lethal screens, by siRNA, the CRISPR/Cas9 system or small
molecules, can be used to identify genes or small-molecule compounds to
specifically target tumour cells (22, 23). The
tumor suppressor PTEN regulates cell migration, survival, growth and DNA damage
response (24,
25). PTEN
is inactivated in several cancers including 30-50% of CRC cases (26-28). It has been shown that
loss of PTEN protein expression is associated with treatment failure by
cetuximab, trastuzumab and erlotinib (29-33). PTEN mutations also
affect genome stability (34). C-terminus of PTEN,
independent of its phosphatase activity, is essential to maintain
heterochromatin structure (35). PTEN deficiency causes a
defect of DNA DSB repair by HR (36). Therefore,
PTEN-deficient tumors should be considered an excellent target for a synthetic
lethality approach to treatment. PARP has been shown to be a synthetic lethal
partner of PTEN when cells lacking PTEN were found to be sensitive to the PARP
inhibitor KU0058948 (36).

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Similarly, it was confirmed that PNKP
inhibition by the small molecule A12B4C3 in PC3 prostate cancer cell line,
naturally deficient in PTEN, and HCTT116 depleted of PTEN cause synthetic
lethality (37). In Chapter 3, we have
also demonstrated that the newly found inhibitors A12B4C50 and A83B4C63 exhibit
synthetic lethality with PTEN-deficient cells. The mechanism of lethality
between PNKP and PTEN is not determined yet. However, there is a possibility
that because PTEN deficiency causes impairment to the HR pathway, the induced
inhibition of PNKP by small molecule inhibitors disrupts both SSB repair as
well as NHEJ, therefore causing cell death.  

Synthetic lethality will provide us with more
personalized treatment for each cancer patient. Patients will have their cancer
screened to determine major protein or gene deficiencies. With this information
it will be possible to match synthetic lethal associations and assigning the
best personalized treatment. For example, PTEN status in mCRC is a valuable predictive
biomarker for monoclonal antibodies targeting epidermal growth factor receptor
in chemotherapy (38). Therefore, if a CRC patient was found to
harbor inactive PTEN the oncologist should design a suitable treatment for the
patient, and potentially this treatment will include the use of PNKP novel
inhibitors as synthetic lethal treatment. Figure 5.1 confirms the above argument. mCRC Patients
with deficient PTEN were not responsive to the administered anti-EGFR treatment