Version 1
: Received: 1 August 2023 / Approved: 2 August 2023 / Online: 3 August 2023 (08:14:08 CEST)
Version 2
: Received: 28 August 2023 / Approved: 30 August 2023 / Online: 31 August 2023 (09:23:31 CEST)
Version 3
: Received: 19 September 2023 / Approved: 20 September 2023 / Online: 21 September 2023 (08:46:22 CEST)
How to cite:
Bhoir, S.; Ogundepo, O.; Yu, X.; De benedetti, A. Exploiting TLK1 and Cisplatin Synergy for Synthetic Lethality in Androgen-Insensitive Prostate Cancer. Preprints2023, 2023080250. https://doi.org/10.20944/preprints202308.0250.v1
Bhoir, S.; Ogundepo, O.; Yu, X.; De benedetti, A. Exploiting TLK1 and Cisplatin Synergy for Synthetic Lethality in Androgen-Insensitive Prostate Cancer. Preprints 2023, 2023080250. https://doi.org/10.20944/preprints202308.0250.v1
Bhoir, S.; Ogundepo, O.; Yu, X.; De benedetti, A. Exploiting TLK1 and Cisplatin Synergy for Synthetic Lethality in Androgen-Insensitive Prostate Cancer. Preprints2023, 2023080250. https://doi.org/10.20944/preprints202308.0250.v1
APA Style
Bhoir, S., Ogundepo, O., Yu, X., & De benedetti, A. (2023). Exploiting TLK1 and Cisplatin Synergy for Synthetic Lethality in Androgen-Insensitive Prostate Cancer. Preprints. https://doi.org/10.20944/preprints202308.0250.v1
Chicago/Turabian Style
Bhoir, S., Xiuping Yu and Arrigo De benedetti. 2023 "Exploiting TLK1 and Cisplatin Synergy for Synthetic Lethality in Androgen-Insensitive Prostate Cancer" Preprints. https://doi.org/10.20944/preprints202308.0250.v1
Abstract
Cellular organisms possess intricate DNA damage repair and tolerance pathways to manage various DNA lesions arising from endogenous or exogenous sources. Dysregulation of these pathways is associated with cancer development and progression. Synthetic lethality (SL), a promising cancer therapy concept, involves exploiting the simultaneous functional loss of two genes for selective cell death. PARP inhibitors (PARPis) have demonstrated success in BRCA-deficient tumors. Cisplatin (CPT), a widely used chemotherapy agent, forms DNA adducts and crosslinks, rendering it effective against various cancers but less so for prostate cancer (PCa) due to resistance and toxicity. Here, we explore the therapeutic potential of TLK1, a kinase upregulated in androgen-insensitive PCa cells, as a target for enhancing CPT-based therapy. TLK1 phosphorylates key homologous recombination repair (HRR) proteins RAD54L and RAD54B, critical for HRR alongside RAD51. The combination of CPT with TLK1 inhibitor J54 exhibits SL in androgen-insensitive PCa cells. The formation of double-strand break intermediates during inter-strand crosslink processing necessitates HRR for effective repair. Therefore, targeting TLK1 with J54 enhances the SL of CPT by impeding HRR, leading to increased sensitivity in PCa cells. These findings suggest a promising approach for improving CPT-based therapies in PCa, particularly in androgen-insensitive cases. By elucidating the role of TLK1 in CPT resistance, this study provides valuable insights into potential therapeutic targets to overcome PCa resistance to CPT chemotherapy. Further investigations into TLK1 inhibition in combination with other DNA-damaging agents may pave the way for more effective and targeted treatments for PCa and other cancers that exhibit resistance to traditional chemotherapy agents.
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
