Abstract 6388: MERTK and ROCK inhibitors mediate synergistic AML cell death and enhance therapeutic activity in combination with cytotoxic chemotherapy

Survival rates are suboptimal for adult and pediatric patients with acute myeloid leukemia (AML). Cytotoxic chemotherapies have short and long-term side effects and are often contraindicated for elderly patients. Targeted agents can reduce toxicity compared to chemotherapy; however, resistance to single-agents often develops, thus combination therapies may provide more durable responses. To increase efficacy and reduce exposure to cytotoxic agents, a targeted combination therapy (MERTK/ROCKi) was utilized alone and with doxorubicin or etoposide, frontline cytotoxic chemotherapeutics routinely used for AML treatment. MERTK is aberrantly expressed in >80% of AML patient samples and MERTK inhibitors are in clinical development. Both MERTK and rho-associated, coiled-coil-containing protein kinases 1 and 2 (ROCK1/2) regulate actin/microtubule dynamics and cell cycle progression and shMERTK or siROCK1 knockdown induces apoptosis in AML cells. Here, analysis of The Cancer Genome Atlas database revealed poorer overall survival in patients with higher levels of ROCK1 mRNA (p Citation Format: Dawn E. Barnes, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Deborah DeRyckere, Douglas K. Barnes. MERTK and ROCK inhibitors mediate synergistic AML cell death and enhance therapeutic activity in combination with cytotoxic chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6388.