Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are effective against ALK-driven cancers.
• Resistance to ALK TKIs limits their clinical use, especially in anaplastic large cell lymphoma (ALCL).
• Mechanisms of ALK TKI resistance in ALCL are not well understood.

Purpose of the Study:

• To identify resistance mechanisms in ALK-driven ALCL.
• To investigate the role of the tumor microenvironment in ALK TKI resistance.
• To explore therapeutic strategies targeting resistance pathways in ALCL.

Main Methods:

• Analysis of PI3K signaling in ALCL patients and cell lines resistant to ALK TKIs.
• Investigated the role of C-C motif chemokine receptor 7 (CCR7) and PI3K isoforms (PI3Kγ, PI3Kδ) in resistance.
• Utilized a three-dimensional microfluidic chip model with endothelial cells.
• Tested the efficacy of PI3Kγ/δ inhibitor duvelisib in combination with ALK TKI crizotinib.
• Assessed the impact of CCR7 deletion on ALCL dissemination and growth in mice.

Main Results:

• Increased PI3K signaling was observed in ALCL patients and cell lines resistant to ALK TKIs.
• PI3Kγ expression predicted poor response to ALK TKI treatment in ALCL patients.
• CCR7, PI3Kγ, and PI3Kδ were upregulated upon ALK or STAT3 inhibition.
• Endothelial cells producing CCR7 ligands protected ALCL cells from crizotinib-induced apoptosis.
• Duvelisib potentiated crizotinib activity against ALCL.
• CCR7 deletion reduced ALCL central nervous system dissemination and perivascular growth in mice.

Conclusions:

• A tumor microenvironment-mediated survival pathway involving CCR7 and PI3Kγ signaling contributes to ALK TKI resistance in ALCL.
• Combined blockade of PI3Kγ or CCR7 signaling with ALK TKI treatment can overcome primary resistance and eliminate persister lymphoma cells in ALCL.