DYRK1A inhibition sensitizes SMARCA4 mutated ALL cells to chemotherapy drugs
Mentor Name: Christian Hurtz
The overall survival rate of children with acute lymphoblastic leukemia (ALL) has significantly improved over the last decade, but children who are diagnosed with KMT2A-rearranged (KMT2A-R) or CRLF2-R ALL (Ph-like ALL) are still experiencing poor clinical outcomes. Our lab recently demonstrated that Dual Specific Tyrosine Regulated Kinase 1A (DYRK1A) is required for KMT2A-R ALL cell proliferation and survival. A similar necessity of DYRK1A has been observed in other subtypes of ALL; however, not every ALL cell line or patient derived xenograft (PDX) sample is sensitive to DYRK1A, and it is not understood why. To elucidate if specific mutations render ALL cells dependent on DYRK1A, we performed DNA-single cell experiments using pediatric PDX cases that we either treated with vehicle control or the novel DYRK1A inhibitor GNF2133. Strikingly, the sequencing results demonstrated that DYRK1A inhibition specifically reduced ALL clones with inactivating mutations in SMARCA4. Reports indicate that loss of SMARCA4 function renders cancer cells resistant to chemotherapy-induced apoptosis. Based on these results, we hypothesize that DYRK1A inhibition selectively kills ALL cells with inactivating SMARCA4 mutations and consequently renders surviving ALL clones expressing functional SMARCA4 sensitive to chemotherapy drugs. The goal of the proposed study is to further elucidate the importance of inactivating SMARCA4 mutations for a successful DYRK1A inhibitor-based therapy.
