November 19, 2019

The one of the most commonly mutated genes in

The tumor suppressor gene,
phosphatase and tensin homolog (PTEN), which is located on human chromosome
10q23, is one of the most commonly mutated genes in several cancer types (178, 179). PTEN regulates many cellular processes through its lipid
phosphatase activity such as cell survival, metabolism, microenvironment and
proliferation (Figure 1.11). Mechanisms controlling PTEN expression and its
activity, including transcription factors and phosphorylation, are often poorly
regulated in cancer (179-181). Recent evidence also indicates that PTEN is important for
the maintenance of genome stability (182). Similar to BRCA, PTEN was found to be a synthetic lethal
partner of PARP (183). A combination of the PARP inhibitor, Olaparib, and cisplatin
showed a synergistic effect in PTEN-deficient lung cancer and endometrial
adenocarcinoma (184, 185). In another study, it was suggested that PTEN
deficiency causes an HR defect in tumor cells (186, 187). In PTEN-deficient cells, inhibition of ATM, a key player in
DDR, by a small molecule exhibited synthetic lethality. It was concluded that
the reason behind this lethality is that elevated levels of ROS due to absence
of PTEN, increased endogenous DNA damage, and therefore ATM inactivation led to
accumulation of drastic DNA damage (188).

In recent years, a new
synthetic lethal partner of PTEN has emerged. An siRNA-based screen of the
~7000-gene “druggable genome” led to the identification of PTEN (and another
tumor suppressor, protein tyrosine phosphatase SHP-1) as a synthetic lethal
partner of PNKP in A549 lung cancer cells (189). Subsequent work showed that PTEN-deficient HCT116 colon
cancer cells were sensitive to A12B4C3 (Figure 1.12), and also dramatically
sensitized PTEN-deficient cells to ionizing radiation (190). The mechanism responsible for the synthetic lethal
partnership between PTEN and PNKP has not yet been fully elucidated.

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PTEN is of interest
clinically for synthetic lethality in many cancers including colorectal cancer
(CRC). Monoallelic mutations at position 10q23 is found in 50-80% of sporadic
cancers such as glioblastoma and prostate cancer and 30-50% in colon and lung
cancers (178). One study demonstrated that PTEN alteration through genetic
or epigenetic mechanisms, such as mutations and promoter hypermethylation,
causes biallelic inactivation of PTEN in 20-30% of CRC patients (191).  Another group
reported that PTEN is inactivated either by loss or reduction of expression in
~70% of CRCs, and this is frequently caused by microsatellite instability (MSI)
(192). MSI in CRC contributes to loss, reduction or inactivation
of PTEN protein levels, thus resulting in tumor progression (193-195). In a recent study, it was found that microRNA-26b promotes
CRC metastasis by down-regulating PTEN (196).  In addition,
mutations or loss of PTEN leads to upregulation of the oncogenic PI3K/AKT
pathways (197, 198), and knockdown of PTEN induces invasion and migration of
HCT116 cells through epithelial mesenchymal transition (EMT) (199). Failure of anti-EGFR treatment, a prominent targeted
therapy, in metastatic CRC (mCRC) has been attributed to the loss of PTEN (200-202). The studies mentioned above all highlight that irregular or
absent functions of PTEN probably contribute significantly to CRC progression
and metastasis, therefore we investigated if the newly identified PNKP
inhibitors could elicit synthetic lethality in CRCs lacking PTEN.


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