Combination of Eribulin and Aurora A Inhibitor MLN8237 Prevents Metastatic Colonization and Induces Cytotoxic...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Aurora A kinase (AURKA) inhibition is a potential strategy for metastatic cancers.
• Triple-negative breast cancer (TNBC) presents significant treatment challenges, particularly in its metastatic forms.

Purpose of the Study:

• To investigate the effects of AURKA inhibition using MLN8237, alone and combined with eribulin, on metastasis in TNBC.
• To elucidate the underlying mechanisms of MLN8237's antimetastatic action.

Main Methods:

• Utilized the small molecule inhibitor MLN8237 and the microtubule-targeting drug eribulin in preclinical models of TNBC.
• Assessed the impact on cancer cell migration, attachment, proliferation, and metastatic colonization.
• Investigated the molecular pathways involved, including autophagy (LC3B/p62 axis) and apoptosis (pAKT).

Main Results:

• MLN8237 monotherapy and combination with eribulin suppressed multiple metastatic steps, including migration and proliferation, reducing colonization and recurrence.
• Eribulin treatment increased active AURKA in TNBC cells, supporting the rationale for combination therapy.
• AURKA inhibition induced cytotoxic autophagy via the LC3B/p62 axis and pAKT inhibition, eradicating metastases but not affecting primary tumor growth.
• The combination synergistically increased apoptosis in primary tumors and induced cytotoxic autophagy in metastases.

Conclusions:

• MLN8237 demonstrates antimetastatic effects by targeting key steps in cancer spread.
• The combination of MLN8237 and eribulin exhibits synergistic effects, offering a promising therapeutic strategy for metastatic breast cancer.
• These findings support the clinical investigation of this combination therapy for metastatic breast cancer and other solid tumors.