Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although survival rates have improved, patients
with certain biological subtypes still have suboptimal outcomes. Current chemotherapeutic regimens are associated with short-
and long-term toxicities and novel, less toxic therapeutic strategies are needed. Mer receptor tyrosine kinase is ectopically
expressed in ALL patient samples and cell lines. Inhibition of Mer expression reduces pro-survival signaling, increases chemosensitivity,
and delays development of leukemia in vivo suggesting that Mer tyrosine kinase inhibitors are excellent candidates for targeted
therapies. Brain and spinal tumors are the second most common malignancies in childhood. Multiple chemotherapy approaches
and radiation have been attempted, yet overall survival remains dismal. Mer is also abnormally expressed in atypical teratoid/rhabdoid
tumors (ATRT), providing a rationale for targeting Mer as a therapeutic strategy. We have previously described UNC569, the
first small molecule Mer inhibitor. This manuscript describes the biochemical and biological effects of UNC569 in ALL and
ATRT. UNC569 inhibited Mer activation and downstream signaling through ERK1/2 and AKT, determined by western blot analysis.
Treatment with UNC569 reduced proliferation/survival in liquid culture, decreased colony formation in methylcellulose/soft
agar, and increased sensitivity to cytotoxic chemotherapies. MYC transgenic zebrafish with T-ALL were treated with UNC569
(4 µM for 2 weeks). Fluorescence was quantified as indicator of the distribution of lymphoblasts, which express Mer and enhanced
green fluorescent protein. UNC569 induced >50% reduction in tumor burden compared to vehicle- and mock-treated fish. These
data support further development of Mer inhibitors as effective therapies in ALL and ATRT.