Aurora A Kinase Inhibition Is Synthetic Lethal with Loss of the RB1 Tumor Suppressor Gene

Area of Science:

• Molecular oncology
• Cancer therapeutics
• Cell cycle regulation

Background:

• Loss-of-function mutations in the retinoblastoma gene (RB1) are prevalent in treatment-refractory cancers like small-cell lung cancer and triple-negative breast cancer.
• Identifying synthetic lethal interactions with RB1 mutations is crucial for developing targeted therapies.

Purpose of the Study:

• To identify cell-cycle inhibitors that are synthetically lethal with RB1 mutations (RB1mut).
• To evaluate the therapeutic potential of Aurora kinase A (AURKA) inhibition in RB1-deficient cancers.

Main Methods:

• Screened 36 cell-cycle inhibitors using a cancer cell panel profiling approach.
• Utilized genetic suppression screens to identify key pathways involved in drug sensitivity.
• Assessed drug efficacy and toxicity in vitro and in vivo using RB1mut cancer cell lines and tumor xenografts.

Main Results:

• Aurora kinases AURKA and AURKB inhibitors showed the strongest association with RB1 mutations.
• LY3295668, a selective AURKA inhibitor, demonstrated minimal bone marrow toxicity and induced durable regression of RB1mut xenografts.
• Enforcers of the spindle-assembly checkpoint (SAC) were essential for LY3295668 cytotoxicity in RB1-deficient cancers.

Conclusions:

• A synthetic lethal interaction exists between RB1 deficiency and AURKA inhibition.
• LY3295668 offers a potential new therapeutic strategy for RB1-deficient malignancies, including those progressing on CDK4/6 inhibitors.
• Continuous dosing of LY3295668 achieves uninterrupted AURKA inhibition without myelosuppression.