Rb, Aurora A, and TRIP13 are all proteins that control various aspects of the cell cycle - a process by which cancer cells divide and grow. Many common, lethal cancer types are driven by the inactivation of Rb (i.e., these cancers are Rb-deficient). We showed that Rb-deficient cancer cells are more sensitive than Rb-proficient cancer cells to the combination Aurora A and TRIP13 inhibition. The combination of Aurora A and TRIP13 inhibition caused cancer cell death (apoptosis) in a way that can stimulate the immune system (immunogenic cell death, ICD) in Rb-deficient but not in non-cancer cells. We hypothesize that by sparing normal cells, which naturally express Rb, the combination of Aurora ...

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Rb, Aurora A, and TRIP13 are all proteins that control various aspects of the cell cycle - a process by which cancer cells divide and grow. Many common, lethal cancer types are driven by the inactivation of Rb (i.e., these cancers are Rb-deficient). We showed that Rb-deficient cancer cells are more sensitive than Rb-proficient cancer cells to the combination Aurora A and TRIP13 inhibition. The combination of Aurora A and TRIP13 inhibition caused cancer cell death (apoptosis) in a way that can stimulate the immune system (immunogenic cell death, ICD) in Rb-deficient but not in non-cancer cells. We hypothesize that by sparing normal cells, which naturally express Rb, the combination of Aurora A and TRIP13 inhibition will be well tolerated by humans but still kill Rb-deficient cancer cells. Additionally, the ICD induced by this combination will lead to immune cell engagement, thereby enhancing tumor elimination. Completion of our Aims will fill the gaps in knowledge that hinder clinical translation of this combination. The mechanism that leads to apoptosis is unknown (Aim 1: "Define the mechanism underlying the synthetic lethality of TRIP13 and Aurora kinase A in Rb-deficient cancer cells"). The effect of the combination on the tumor immune microenvironment (TIME) is unknown (Aim 2: "Characterize the impact of TRIP13/Aurora A dual inhibition on the TIME and identify mechanisms of immune vulnerability induced by combination therapy"). Preclinical and clinical research are hampered by the lack of a specific TRIP13 inhibitor (Aim 3: "To evaluate novel, potent and selective small molecule inhibitors of TRIP13"). The use of this combination for the treatment of any cancer has not been studied. Our research will establish a foundation for future clinical trials whose results may change clinical practice paradigms. Clinical translation of the combination is feasible, as Aurora A inhibitors are in clinical testing, and TRIP13 is potentially druggable.

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