Biomarkers of dasatinib response and resistance in T-cell acute lymphoblastic leukemia

Abstract Acute lymphoblastic leukemia (ALL) is the most common cancer in children, with T-cell ALL accounting for 15% of cases. T-ALL in children is associated with aggressive clinical features and inferior treatment response to combination chemotherapy, compared to B-cell ALL. Further intensification of cytotoxic drug-based therapy is ineffective for relapsed T-ALL and novel agents are much needed for these patients. We recently discovered that a significant proportion of pediatric T-ALL exhibits exceptional response to tyrosine kinase inhibitor dasatinib, in an ABL-independent fashion. Our preliminary genomic analyses pointed to the activation of the preTCR-LCK signaling pathway as a potential driver of this drug response phenotype. We have developed an innovative systems biology approach that integrates transcriptional profile with functional ex vivo drug testing in order to develop a clinically translatable biomarker for sensitivity and resistance to dasatinib in T-ALL. We hypothesize that our systems biology approach can comprehensively identify molecular determinants of dasatinib response in T-ALL, and that dasatinib-sensitive T-ALLs have distinct clinical and genomic features. In this project, we propose to 1) develop a systems biology-based biomarker model of dasatinib sensitivity in T- ALL; 2) systematically characterize genomics and clinical features associated with dasatinib sensitivity in T-ALL, and 3) explore mechanism of dasatinib resistance in T-ALL and develop biomarker-driven combination therapy to overcome drug resistance. Successful completion of these studies is likely to substantially shift the paradigm of how pediatric T-ALL is treated and significantly impact the next generation of clinical trials and improve cure rates for children with this devastating illness.