Differential Chemoproteomics Reveals MARK2/3 as Cell Migration-Relevant Targets of the ALK Inhibitor Brigatinib

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Metastasis is a significant challenge in managing non-small cell lung cancer (NSCLC), particularly in cases with EML4-ALK rearrangements.
• Cell migration is a crucial process in cancer metastasis.

Purpose of the Study:

• To investigate the anti-migratory activities of clinical ALK inhibitors in NSCLC cells.
• To identify the molecular targets responsible for brigatinib's superior anti-migratory effects.

Main Methods:

• Assessed anti-migratory capabilities of ALK inhibitors in NSCLC cells.
• Utilized in situ mass spectrometry-based chemoproteomics to determine brigatinib's proteome-wide target profile.
• Performed functional validation through pharmacological inhibition and genetic modulation of identified targets.

Main Results:

• Brigatinib demonstrated superior anti-migratory effects compared to other ALK inhibitors, despite similar ALK inhibition.
• Chemoproteomics identified MARK2 and MARK3 as relevant brigatinib kinase targets.
• Inhibition of MARK2/3 significantly reduced cell migration and led to inhibitory YAP1 phosphorylation downstream.

Conclusions:

• Brigatinib exhibits cross-phenotype polypharmacology by co-targeting EML4-ALK and MARK2/3 kinases.
• This dual targeting contributes to brigatinib's enhanced efficacy in preventing NSCLC cell migration.
• Brigatinib represents a promising therapeutic strategy for inhibiting metastasis in ALK-rearranged NSCLC.