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Differential Chemoproteomics Reveals MARK2/3 as Cell Migration-Relevant Targets of the ALK Inhibitor Brigatinib |
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| Authors: | Qianqian Hu Yi Liao Jessica Cao Bin Fang Sang Y Yun Fumi Kinose Eric B Haura Harshani R Lawrence Robert C Doebele John M Koomen Uwe Rix |
| Affiliation: | 1. Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, 33612 USA
Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL-33620 USA;2. Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, 33612 USA;3. Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, 33612 USA;4. Chemical Biology Core (Chemistry Unit), H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, 33612 USA;5. Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, 33612 USA;6. Chemical Biology Core (Chemistry Unit), H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, 33612 USA Department of Oncologic Sciences, University of South Florida, Tampa, Florida, 33620 USA;7. Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045 USA;8. Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, 33612 USA Department of Oncologic Sciences, University of South Florida, Tampa, Florida, 33620 USA |
| Abstract: | Metastasis poses a major challenge in cancer management, including EML4-ALK-rearranged non-small cell lung cancer (NSCLC). As cell migration is a critical step during metastasis, we assessed the anti-migratory activities of several clinical ALK inhibitors in NSCLC cells and observed differential anti-migratory capabilities despite similar ALK inhibition, with brigatinib displaying superior anti-migratory effects over other ALK inhibitors. Applying an unbiased in situ mass spectrometry-based chemoproteomics approach, we determined the proteome-wide target profile of brigatinib in EML4-ALK+ NSCLC cells. Dose-dependent and cross-competitive chemoproteomics suggested MARK2 and MARK3 as relevant brigatinib kinase targets. Functional validation showed that combined pharmacological inhibition or genetic modulation of MARK2/3 inhibited cell migration. Consistently, brigatinib treatment induced inhibitory YAP1 phosphorylation downstream of MARK2/3. Collectively, our data suggest that brigatinib exhibits unusual cross-phenotype polypharmacology as, despite similar efficacy for inhibiting EML4-ALK-dependent cell proliferation as other ALK inhibitors, it more effectively prevented migration of NSCLC cells due to co-targeting of MARK2/3. |
| Keywords: | brigatinib chemoproteomics MARK3 migration polypharmacology |