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Published on: September 3, 2021
Longitudinal phosphoproteomics reveals the PI3K-PAK1 axis as a potential target for recurrent colorectal liver
Daigo Gunji1, Yuichi Abe2, Satoshi Muraoka3
1Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan; Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
Abstract:
The resistance of colorectal cancer liver metastases (CRLMs) to 5-fluorouracil (5-FU) chemotherapy remains a significant global health challenge. We investigated the phosphoproteomic dynamics of serial tissue sections obtained from initial metastases and recurrent tumors collected from 24 patients to address this unmet need for innovative therapeutic strategies for patients with CRLM with a poor prognosis. Our analysis revealed the activation of PAK kinase in patients with CRLM with a poor prognosis. Using an unbiased computational approach, we conducted a correlation analysis between PAK1 kinase activity and 545 drug sensitivity profiles across 35 colorectal cancer cell lines and identified PI3K inhibitors as potential therapeutic candidates. The efficacy of the FDA-approved PI3K inhibitor copanlisib was validated in 5-FU-resistant cell lines with high PAK1 kinase activity both in vitro and in vivo. This study presents an effective strategy for drug target discovery based on kinase activity, and the concept of this approach is widely applicable.
Insights
Colorectal cancer liver metastases resistant to 5-FU chemotherapy show activated PAK kinase. PI3K inhibitors, like copanlisib, show promise for treating these resistant tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Colorectal cancer liver metastases (CRLMs) often develop resistance to 5-fluorouracil (5-FU) chemotherapy, posing a significant challenge.
- Innovative therapeutic strategies are needed for patients with poor-prognosis CRLM.
Purpose of the Study:
- To investigate phosphoproteomic dynamics in CRLM to identify therapeutic targets.
- To discover novel therapeutic strategies for 5-FU-resistant CRLM.
Main Methods:
- Phosphoproteomic analysis of serial tissue sections from 24 patients with initial and recurrent CRLM.
- Computational correlation analysis between PAK1 kinase activity and drug sensitivity in 35 colorectal cancer cell lines.
- In vitro and in vivo validation of PI3K inhibitor copanlisib efficacy in 5-FU-resistant cell lines.
Main Results:
- PAK kinase activation was identified in patients with poor-prognosis CRLM.
- PI3K inhibitors were identified as potential therapeutic candidates targeting PAK1 activity.
- Copanlisib demonstrated efficacy in 5-FU-resistant CRLM models with high PAK1 activity.
Conclusions:
- Kinase activity profiling is an effective strategy for drug target discovery.
- PI3K inhibitors, specifically copanlisib, offer a potential therapeutic approach for 5-FU-resistant CRLM.
- This kinase-activity-based drug discovery approach has broad applicability.
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