TBK1 Reprograms Metabolism in Breast Cancer: An Integrated Omics Approach

Metabolic
rewiring is required for cancer cells to survive
in harsh
microenvironments and is considered to be a hallmark of cancer. Specific
metabolic adaptations are required for a tumor to become invasive
and metastatic. Cell division and metabolism are inherently interconnected,
and several cell cycle modulators directly regulate metabolism. Here,
we report that TBK1, which is a noncanonical IKK kinase with known
roles in cell cycle regulation and TLR signaling, affects cellular
metabolism in cancer cells. While TBK1 is reported to be overexpressed
in several cancers and its enhanced protein level correlates with
poor prognosis, the underlying molecular mechanism involved in the
tumor-promoting role of TBK1 is not fully understood. In this study,
we show a novel role of TBK1 in regulating cancer cell metabolism
using combined metabolomics, transcriptomics, and pharmacological
approaches. We find that TBK1 mediates the regulation of nucleotide
and energy metabolism through aldo-keto reductase B10 (AKRB10) and
thymidine phosphorylase (TYMP) genes, suggesting that this TBK1-mediated
metabolic rewiring contributes to its oncogenic function. In addition,
we find that TBK1 inhibitors can act synergistically with AKRB10 and
TYMP inhibitors to reduce cell viability. These findings raise the
possibility that combining these inhibitors might be beneficial in
combating cancers that show elevated levels of TBK1.