Related Experiment Video

Updated: May 30, 2025

Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
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Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer

Published on: August 2, 2024

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Identification of a TNIK-CDK9 Axis as a Targetable Strategy for Platinum-Resistant Ovarian Cancer

Noah Puleo1,2,3, Harini Ram1,2, Michele L Dziubinski1,2

  • 1Department of Pathology, University of Michigan, Ann Arbor, Michigan.

Molecular Cancer Therapeutics
|January 28, 2025
PubMed

Insights

Artificial intelligence identified the TNIK-CDK9 axis as novel targets for overcoming platinum resistance in high-grade serous ovarian cancer (HGSC). Targeting this pathway with NCB-0846 shows promise for improving patient outcomes.

Area of Science:

  • Oncology
  • Drug Discovery
  • Genomics

Background:

  • High-grade serous ovarian cancer (HGSC) frequently develops platinum chemotherapy resistance, necessitating new therapeutic strategies.
  • Lack of universally druggable targets complicates treatment for platinum-resistant HGSC.
  • Artificial intelligence (AI) offers a novel approach for identifying therapeutic targets.

Purpose of the Study:

  • To identify novel therapeutic targets for platinum-resistant HGSC using AI-driven drug discovery.
  • To investigate the efficacy of targeting TNIK with NCB-0846 in platinum-resistant HGSC models.
  • To elucidate the mechanisms underlying platinum resistance and the action of NCB-0846.

Main Methods:

  • AI-driven screening of therapeutic targets and tool compounds in patient-derived 3D models.
  • In vitro and ex vivo organoid studies to assess compound efficacy.
  • AI, in silico, and in vitro analyses to identify key targets and pathways.
  • Correlation analysis of gene expression and chromosomal gains with patient outcomes.

Main Results:

  • TNIK, modulated by NCB-0846, was identified as a novel target for platinum-resistant HGSC.
  • NCB-0846 demonstrated efficacy in platinum-resistant HGSC models and reduced Wnt activity.
  • CDK9 was identified as a key target mediating NCB-0846's efficacy, independent of TNIK inhibition alone.
  • Combined TNIK and CDK9 inhibition reduced Wnt targets and chemotherapy-resistant cell viability.
  • TNIK and CDK9 co-expression and chromosomal gains correlated with poor patient prognosis.

Conclusions:

  • The TNIK-CDK9 axis represents a druggable target for overcoming platinum resistance in HGSC.
  • CDK9 is a novel mediator of canonical Wnt activity, contributing to platinum resistance.
  • AI combined with physiologically relevant models is effective for target discovery and validation in oncology.
  • This study provides mechanistic insights into NCB-0846 and CDK9 inhibitor function, paving the way for new therapeutic strategies.

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