Unbiased discovery of cancer pathways and therapeutics using Pathway Ensemble Tool and Benchmark

Luopin Wang, Aryamav Pattnaik, Subhransu Sekhar Sahoo, Ella G. Stone, Yuxin Zhuang, Annaleigh Benton, Md Tajmul, Srishti Chakravorty, Deepika Dhawan, My An Nguyen, Isabella Sirit, Kyle Mundy, Christopher J. Ricketts, Marco Hadisurya, Garima Baral, Samantha L. Tinsley, Nicole L. Anderson, Smriti Hoda, Scott D. Briggs, Hristos Z. Kaimakliotis, Brittany L. Allen-Petersen, W. Andy Tao, W. Marston Linehan, Deborah W. Knapp, Jason A. Hanna, Matthew R. Olson, Behdad Afzali () and Majid Kazemian ()
Additional contact information
Luopin Wang: Purdue University
Aryamav Pattnaik: Purdue University
Subhransu Sekhar Sahoo: Purdue University
Ella G. Stone: Purdue University
Yuxin Zhuang: Purdue University
Annaleigh Benton: Purdue University
Md Tajmul: Purdue University
Srishti Chakravorty: Purdue University
Deepika Dhawan: Purdue University
My An Nguyen: Purdue University
Isabella Sirit: Purdue University
Kyle Mundy: Purdue University
Christopher J. Ricketts: National Cancer Institute (NCI), NIH
Marco Hadisurya: Purdue University
Garima Baral: Purdue University
Samantha L. Tinsley: Purdue University
Nicole L. Anderson: Purdue University
Smriti Hoda: Purdue University
Scott D. Briggs: Purdue University
Hristos Z. Kaimakliotis: Indiana University
Brittany L. Allen-Petersen: Purdue University
W. Andy Tao: Purdue University
W. Marston Linehan: National Cancer Institute (NCI), NIH
Deborah W. Knapp: Purdue University
Jason A. Hanna: Purdue University
Matthew R. Olson: Purdue University
Behdad Afzali: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH
Majid Kazemian: Purdue University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Correctly identifying perturbed biological pathways is a critical step in uncovering basic disease mechanisms and developing much-needed therapeutic strategies. However, whether current tools are optimal for unbiased discovery of relevant pathways remains unclear. Here, we create “Benchmark” to critically evaluate existing tools and find that most function sub-optimally. We thus develop the “Pathway Ensemble Tool” (PET), which outperforms existing methods. Deploying PET, we identify prognostic pathways across 12 cancer types. PET-identified prognostic pathways offer additional insights, with genes within these pathways serving as reliable biomarkers for clinical outcomes. Additionally, normalizing these pathways using drug repurposing strategies represents therapeutic opportunities. For example, the top predicted repurposed drug for bladder cancer, a CDK2/9 inhibitor, represses cell growth in vitro and in vivo. We anticipate that using Benchmark and PET for unbiased pathway discovery will offer additional insights into disease mechanisms across a spectrum of diseases, enabling biomarker discovery and therapeutic strategies.

Date: 2024
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DOI: 10.1038/s41467-024-51859-9

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