Synthetic lethal approaches to target cancers with loss of PTEN function

Phosphatase and tensin homolog ( PTEN) is a tumour suppressor gene and has a role in inhibiting the oncogenic AKT signalling pathway by dephosphorylating phosphatidylinositol 3,4,5-triphosphate (PIP 3) into phosphatidylinositol 4,5-bisphosphate (PIP 2). The function of PTEN is regulated by different mechanisms and inactive PTEN results in aggressive tumour phenotype and tumorigenesis. Identifying targeted therapies for inactive tumour suppressor genes such as PTEN has been challenging as it is difficult to restore the tumour suppressor functions. Therefore, focusing on the downstream signalling pathways to discover a targeted therapy for inactive tumour suppressor genes has highlighted the importance of synthetic lethality studies. This review focuses on the potential synthetic lethality genes discovered in PTEN-inactive cancer types. These discovered genes could be potential targeted therapies for PTEN-inactive cancer types and may improve the treatment response rates for aggressive types of cancer.

Cancer, PTEN, Synthetic lethality, Tumour suppressor gene, WDHD1

10.1016/j.gendis.2022.12.015

2352-3042

2511-2527

Ertay, Ayse

fdd0c5cb-cfb2-4e25-9343-cdc462035531

Ewing, Robert

022c5b04-da20-4e55-8088-44d0dc9935ae

Wang, Yihua

f5044a95-60a7-42d2-87d6-5f1f789e3a7e

November 2023

Ertay, Ayse

fdd0c5cb-cfb2-4e25-9343-cdc462035531

Ewing, Robert

022c5b04-da20-4e55-8088-44d0dc9935ae

Wang, Yihua

f5044a95-60a7-42d2-87d6-5f1f789e3a7e

Ertay, Ayse, Ewing, Robert and Wang, Yihua (2023) Synthetic lethal approaches to target cancers with loss of PTEN function. Genes and Diseases, 10 (6), 2511-2527. (doi:10.1016/j.gendis.2022.12.015).

Record type: Review

Abstract

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PTEN Review_Final - Accepted Manuscript

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Accepted/In Press date: 27 December 2022

e-pub ahead of print date: 1 February 2023

Published date: November 2023

Additional Information: Funding Information: APE1 is another protein that has function in DNA base excision repair (BER) and the synthetic lethal link between PTEN and APE1 was identified in melanoma.158 Abbotts et al in 2014 demonstrated that PTEN-deficient cells have defective gene expressions which play a role in DNA double-strand break (DSB) break compared to the PTEN-proficient cells. Since the sensitivity, accumulation of DSBs, and apoptosis were increased post-treatment of APE1 inhibitors, the synthetic lethality relation between PTEN and APE1 was supported in melanoma.158 This study showed that blocking BER by APE inhibition could be a potential targeted therapy for PTEN-deficient melanomas.This work was supported by an Academy of Medical Sciences, United Kingdom/the Wellcome Trust Springboard Award (No. SBF002\1038) and the Medical Research Council, United Kingdom (No. MR/S025480/1). A.E. was supported by the Wessex Medical Trust, United Kingdom. For the purpose of open access, the authors have applied a CC-BY public copyright license to any Author Accepted Manuscript version arising from this submission. Funding Information: This work was supported by an Academy of Medical Sciences, United Kingdom /the Wellcome Trust Springboard Award (No. SBF002\1038) and the Medical Research Council, United Kingdom (No. MR/S025480/1). A.E. was supported by the Wessex Medical Trust, United Kingdom . For the purpose of open access, the authors have applied a CC-BY public copyright license to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: © 2023 Chongqing Medical University

Keywords: Cancer, PTEN, Synthetic lethality, Tumour suppressor gene, WDHD1

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