Longitudinal phosphoproteomics reveals the PI3K-PAK1 axis as a potential target for recurrent colorectal liver metastases

• Published in: Cell reports (Cambridge) 2024-12, Vol.43 (12), p.115061, Article 115061
• Main Authors: Gunji, Daigo, Abe, Yuichi, Muraoka, Satoshi, Narumi, Ryohei, Isoyama, Junko, Ikemoto, Narumi, Ishida, Mimiko, Shinkura, Akina, Tomonaga, Takeshi, Nagayama, Satoshi, Takahashi, Yu, Fukunaga, Yosuke, Sakai, Yoshiharu, Obama, Kazutaka, Adachi, Jun
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; chemotherapy resistance; colorectal cancer liver metastases; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; computational approaches; drug repositioning; Drug Resistance, Neoplasm - drug effects; Female; Fluorouracil - pharmacology; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Male; Mice; Mice, Nude; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; p21-Activated Kinases - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - metabolism; phosphoproteomic dynamics; Proteomics - methods; Signal Transduction - drug effects
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.115061

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. [Display omitted] •Longitudinal phosphoproteomic profiles track CRLM progression during treatment•The PAK1 signature indicates CRLM aggressiveness in adjuvant chemotherapy•Kinase-activity-based drug selection highlights the PI3K-PAK1 axis in CRC•PI3K inhibition modulates MAPK signaling via PAK1 in 5-FU-resistant CRC models Gunji et al. demonstrated that an increased PAK1 signature correlates with CRLM aggressiveness during chemotherapy using a longitudinal phosphoproteomic approach. Their computational kinase-activity-based drug selection and subsequent in vivo pharmacoproteomic analysis revealed that PI3K inhibition regulates MAPK signaling through PAK1 in a substrate-dependent manner.