Inhibition of branched-chain alpha-keto acid dehydrogenase kinase augments the sensitivity of ovarian and breast cancer cells to paclitaxel

Context: Many cancer patients who initially respond to chemotherapy eventually develop chemoresistance, and to address this, we previously conducted a RNAi screen to identify genes contributing to resistance. One of the hits from the screen was branched-chain alpha-keto acid dehydrogenase kinase (BCKDK). BCKDK controls the metabolism of branched-chain amino acids (BCAAs) through phosphorylation and inactivation of the branched-chain alpha-keto acid dehydrogenase complex (BCKDH), thereby inhibiting catabolism of BCAAs. Methods: We measured the impact on paclitaxel sensitivity of inhibiting BCKDK in ovarian and breast cancer cell lines. Results: Inhibition of BCKDK using siRNA or two chemical inhibitors (BCKDKi) was synergistic with paclitaxel in both breast and ovarian cancer cells. BCKDKi reduced levels of BCAA and the addition of exogenous BCAA suppressed this synergy. BCKDKi inactivated the mTORC1-Aurora pathway, allowing cells to overcame M-phase arrest induced by paclitaxel. In some cases, cells almost completed cytokinesis, then reverted to a single cell, resulting in multinucleate cells. Conclusion: BCKDK is an attractive target to augment the sensitivity of cancer cells to paclitaxel.

Automated summary

Through RNAi screening, we identified a gene called branched-chain alpha-keto acid dehydrogenase kinase (BCKDK) that contributes to chemoresistance, and inhibiting BCKDK can enhance the sensitivity of breast and ovarian cancer cells to paclitaxel by suppressing the metabolism of branched-chain amino acids.