Targeting mitotic exit in solid tumors

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Taxanes are common chemotherapy agents targeting mitosis in solid tumors.
• Cancer cells can survive taxanes via mitotic slippage, a process involving the anaphase-promoting complex (APC/C) and cyclin B degradation.
• Inhibiting proteasome (PI) or APC/C may enhance cancer cell death by prolonging mitotic arrest.

Purpose of the Study:

• To investigate the efficacy of combining taxanes with proteasome or APC/C inhibitors in lung and breast cancer models.
• To determine the cell cycle phase at which cell death occurs under these combination treatments.

Main Methods:

• Utilized various cell lines and patient-derived xenografts (PDX) from lung and breast cancer.
• Administered sequential combinations of paclitaxel with bortezomib (a PI) or APC/C inhibitors.
• Investigated the impact of Mcl-1 inhibition in combination treatments for breast cancer.

Main Results:

• Sequential paclitaxel and bortezomib enhanced cell death in interphase, not mitosis, in both lung and breast cancer.
• APC/C inhibition with paclitaxel induced mitotic cell death in lung cancer.
• In breast cancer with high Mcl-1, combined APC/C and Mcl-1 inhibition with or without paclitaxel induced interphase cell death.

Conclusions:

• Combining antimitotic agents with proteasome, APC/C, or Mcl-1 inhibitors is a promising strategy to improve solid tumor treatment.
• The efficacy and cell cycle phase of cell death are dependent on the specific cancer type and inhibitors used.