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Tousled-like kinase 1: a novel factor with multifaceted role in mCRPC progression and development of therapy

Md Imtiaz Khalil1, Arrigo De Benedetti1

  • 1Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, Shreveport, LA 71103, USA.

Cancer Drug Resistance (Alhambra, Calif.)
|May 18, 2022
PubMed

Insights

Targeting the TLK1 kinase in prostate cancer (PCa) can prevent the development of metastatic castration-resistant prostate cancer (mCRPC) by inhibiting adaptation to androgen deprivation therapy (ADT). This offers a new strategy to improve treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Advanced prostate cancer (PCa) treatment with androgen deprivation therapy (ADT) eventually fails, leading to incurable metastatic castration-resistant prostate cancer (mCRPC).
  • Targeting adaptive pathways that promote mCRPC development before progression is crucial for improving patient outcomes.
  • Current combination therapies targeting the DNA damage response (DDR) with ADT face challenges due to general toxicity, highlighting the need for more specific DDR targeting strategies.

Purpose of the Study:

  • To investigate the role of the DNA damage response (DDR) kinase TLK1 in prostate cancer (PCa) progression to metastatic castration-resistant prostate cancer (mCRPC).
  • To elucidate the specific pathways mediated by TLK1 that facilitate adaptation to androgen deprivation therapy (ADT) and promote mCRPC development.
  • To explore TLK1's involvement in apoptosis, motility, and metastasis in the context of PCa treatment resistance.

Main Methods:

  • Investigated the TLK1>NEK1>ATR>Chk1 kinase cascade in promoting cell cycle arrest during androgen deprivation.
  • Examined the NEK1>YAP/AR>CRPC conversion pathway mediated by TLK1 for androgen-independent growth.
  • Analyzed TLK1's role in apoptosis via NEK1>VDAC1 regulation and its impact on the mitochondrial apoptotic pathway.
  • Studied TLK1's regulation of MK5/PRAK and AKT kinases in relation to PCa cell motility and metastasis.

Main Results:

  • TLK1 promotes cell cycle arrest under androgen deprivation via the TLK1>NEK1>ATR>Chk1 pathway.
  • TLK1 reprograms PCa cells for androgen-independent growth through the NEK1>YAP/AR>CRPC pathway.
  • TLK1 inhibits apoptosis via NEK1>VDAC1 regulation of the intrinsic mitochondrial pathway when DDR is activated.
  • TLK1 influences PCa cell motility and metastasis through regulation of MK5/PRAK and AKT kinases.

Conclusions:

  • TLK1 is a key mediator of PCa adaptation to ADT, driving progression to mCRPC.
  • Targeting TLK1 offers a potential strategy to prevent mCRPC development and overcome treatment resistance.
  • Understanding TLK1's multifaceted roles in cell cycle, apoptosis, and metastasis provides new therapeutic avenues for advanced prostate cancer.
Keywords:
DNA damage responseNEK1TLK1VDAC1YAP1drug resistance in mCRPCmetastatic castration-resistant prostate cancerprostate cancer

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