Targeting human apurinic/apyrimidinic endonuclease 1 (APE1) in phosphatase and tensin homolog (PTEN) deficient melanoma cells for personalized therapy

Abstract

Phosphatase and tensin homolog (PTEN) loss is associated with genomic instability. APE1 is a key player in DNA base excision repair (BER) and an emerging drug target in cancer. We have developed small molecule inhibitors against APE1 repair nuclease activity. In the current study we explored a synthetic lethal relationship between PTEN and APE1 in melanoma. Clinicopathological significance of PTEN mRNA and APE1 mRNA expression was investigated in 191 human melanomas. Preclinically, PTEN-deficient BRAF-mutated (UACC62, HT144, and SKMel28), PTEN-proficient BRAF-wildtype (MeWo), and doxycycline-inducible PTEN-knockout BRAF-wildtype MeWo melanoma cells were DNA repair expression profiled and investigated for synthetic lethality using a panel of four prototypical APE1 inhibitors. In human tumours, low PTEN mRNA and high APE1 mRNA was significantly associated with reduced relapse free and overall survival. Pre-clinically, compared to PTEN-proficient cells, PTEN-deficient cells displayed impaired expression of genes involved in DNA double strand break (DSB) repair. Synthetic lethality in PTEN-deficient cells was evidenced by increased sensitivity, accumulation of DSBs and induction of apoptosis following treatment with APE1 inhibitors. We conclude that PTEN deficiency is not only a promising biomarker in melanoma, but can also be targeted by a synthetic lethality strategy using inhibitors of BER, such as those targeting APE1.

DNA repair targeted therapy: The past or future of cancer treatment?

“…An in silico screening was used to focus on the endonuclease region of APE1 and resulted in the discovery of a series of APE1 inhibitors with varying potency (Mohammed et al, 2011). Similarly, a HTS approach was also used and resulted in the identification of a large number of hits that was subsequently culled to identify cellular activity (Abbotts et al, 2014; Dorjsuren et al, 2012). Srinivasan et.…”

Unveiling the non-repair face of the Base Excision Repair pathway in RNA processing: A missing link between DNA repair and gene expression?

“…Through the redoxmediated activation of NF-ĸB and Hif1α, for example, APE1 indirectly drives IL-8 and VEGF expression, respectively, thus acting as a key regulator of inflammatory and tumor-associated neo-angiogenesis processes. Moreover, APE1 has been implicated in chemoresistance, considering its ability to stimulate the expression of the multi-drug resistance gene MDR1 through the interaction with Y-box-binding protein 1 (YB-1) [53], and its regulatory abilities on the PTEN tumor suppressor [54,55]. We recently characterized a direct role of APE1 in the transcription of SIRT1 gene through the binding of nCaRE-sequences present on its promoter, demonstrating that BER-mediated DNA repair promotes the initiation of transcription of SIRT1 gene upon oxidative DNA damage [41].…”

Apurinic/apyrimidinic endonuclease 1 (APE1/Ref‐1) overexpression is an independent prognostic marker in prostate cancer without TMPRSS2:ERG fusion

“…Upregulation of APE1 has been reported from a multitude of human cancer types, including hepatocellular carcinoma, osteosarcoma, breast, lung, ovarian, colorectal, and bilio‐pancreatic cancer and has been linked to adverse tumor phenotype and poor patient prognosis in some of them . Consequently, APE1 has recently gained interest as an emerging anti‐cancer drug target . APE1 is of particular interest in prostate cancer, because polymorphisms of this gene have been linked to prostate cancer susceptibility .…”