TBK1 Is a Synthetic Lethal Target in Cancer with VHL Loss

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• TANK binding kinase 1 (TBK1) is crucial for innate immune responses.
• The role of TBK1 in cancer, particularly in relation to VHL loss and hypoxia, is not fully understood.

Purpose of the Study:

• To investigate the activation of TBK1 in cancer cells with VHL loss or under hypoxic conditions.
• To explore the therapeutic potential of targeting TBK1 in VHL-deficient kidney cancer.

Main Methods:

• Analysis of TBK1 phosphorylation in patient-derived kidney tumors with VHL loss.
• Genetic ablation and pharmacologic inhibition of TBK1 in cancer cell lines.
• Development and application of a cereblon-based proteolysis targeting chimera (PROTAC) for TBK1 degradation.
• In vivo studies using an orthotopic xenograft model of kidney cancer.
• Mechanistic studies involving protein hydroxylation, binding interactions, and phosphorylation site analysis.

Main Results:

• TBK1 is hyperactivated in cancer cells with VHL loss or hypoxia.
• VHL-deficient kidney cancer cells are sensitive to TBK1 inhibition or depletion, with VHL wild-type cells remaining unaffected.
• TBK1 depletion significantly reduces kidney tumor growth in vivo.
• TBK1 hydroxylation at Proline 48 influences its interaction with VHL and PPM1B, affecting phosphorylation.
• TBK1 phosphorylates p62/SQSTM1 at Ser366, which is vital for p62 stability and cancer cell proliferation.

Conclusions:

• TBK1 activation is linked to VHL loss and hypoxia in cancer, independent of its innate immune function.
• TBK1 represents a promising synthetic lethal target for treating VHL-deficient kidney cancer.
• Targeting TBK1 offers a potential therapeutic strategy for specific cancer subtypes.