The tumor suppressor gene,phosphatase and tensin homolog (PTEN), which is located on human chromosome10q23, is one of the most commonly mutated genes in several cancer types (180, 181). PTEN regulates many cellular processes through its lipidphosphatase activity such as cell survival, metabolism, microenvironment andproliferation (Figure 1.11). Mechanisms controlling PTEN expression and itsactivity, including transcription factors and phosphorylation, are often poorlyregulated in cancer (181-183). Recent evidence also indicates that PTEN is important forthe maintenance of genome stability (184).
Similar to BRCA, PTEN was found to be a synthetic lethalpartner of PARP (185). A combination of the PARP inhibitor, Olaparib, andcisplatin showed a synergistic effect in PTEN-deficient lung cancer andendometrial adenocarcinoma (186, 187). In another study, it was suggested that PTENdeficiency causes an HR defect in tumor cells (188, 189).
In PTEN-deficient cells, inhibition of ATM, a key player inDDR, by a small molecule exhibited synthetic lethality. It was concluded thatthe reason behind this lethality is that elevated levels of ROS due to absenceof PTEN, increased endogenous DNA damage, and therefore ATM inactivation led toaccumulation of drastic DNA damage (190).In recent years, PNKP hasemerged as a new synthetic lethal partner of PTEN. An siRNA-based screen of the~7000-gene “druggable genome” led to the identification of PTEN (and anothertumor suppressor, protein tyrosine phosphatase SHP-1) as a synthetic lethalpartner of PNKP in A549 lung cancer cells (191).
Subsequent work showed that PTEN-deficient HCT116 coloncancer cells were sensitive to A12B4C3 (Figure 1.12), and also dramaticallysensitized PTEN-deficient cells to ionizing radiation (192). The mechanism responsible for the synthetic lethalpartnership between PTEN and PNKP has not yet been fully elucidated.
PTEN is of interestclinically for synthetic lethality in many cancers including colorectal cancer(CRC). Monoallelic mutations at position 10q23 are found in 50-80% of sporadiccancers such as glioblastoma and prostate cancer and 30-50% in colon and lungcancers (180). One study demonstrated that PTEN alteration through geneticor epigenetic mechanisms, such as mutations and promoter hypermethylation,causes biallelic inactivation of PTEN in 20-30% of CRC patients (193). Another groupreported that PTEN is inactivated either by loss or reduction of expression in~70% of CRCs, and this is frequently caused by microsatellite instability (MSI)(194). MSI in CRC contributes to loss, reduction or inactivationof PTEN protein levels, thus resulting in tumor progression (195-197). In a recent study, it was found that microRNA-26b promotesCRC metastasis by down-regulating PTEN (198). In addition,mutations or loss of PTEN leads to upregulation of the oncogenic PI3K/AKTpathways (199, 200), and knockdown of PTEN induces invasion and migration ofHCT116 cells through epithelial mesenchymal transition (EMT) (201).
Failure of anti-EGFR treatment, a prominent targetedtherapy, in metastatic CRC (mCRC) has been attributed to the loss of PTEN (202-204). The studies mentioned above all highlight that irregular orabsent functions of PTEN probably contribute significantly to CRC progressionand metastasis, therefore we investigated if the newly identified PNKPinhibitors could elicit synthetic lethality in CRC cells lacking PTEN.
