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Updated: May 30, 2025
09:40
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
Summary
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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