Precision systems medicine using real-time translation of tailored therapeutic opportunities arising from functional and molecular profiling in acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive disease of proliferative myeloid progenitors needs effective treatment options. Recent FDA approval of several targeted drugs, for AML patients with specific mutations, has raised hope for the patients. However, the response rates in mutation stratified patients are limited. To address the challenge, we integrated genomic and transcriptomic profiling with ex vivo drug responses as part of a real-time approach to identify and translate novel targeted therapeutic options in AML. Comprehensive response profiles to 515 emerging and clinical cancer drugs in 164 patient samples revealed clinically actionable effective and approved targeted drugs in AML. We identified 142 statistically significant association between ex vivo drug responses and mutations including increased sensitivity to JAK inhibitors in patients with NPM1 and IDH1/IDH2 double mutant cases. Transcriptomic profiles predicted drug responses better than genomics and helped to identify additional response biomarkers over genomics. The molecular subset specific analyses revealed transcriptomic features associated with drug responses e.g. HOX gene overexpression and sensitivity to JAK inhibitors in NPM1 mutated cases and AHR overexpression and MEK sensitivity in KRAS/NRAS wild type cases. In a prospective clinical study, we implemented pharmacogenomic data to tailor treatments for late-stage chemorefractory AML patients. In 39% of 26 treatment occasions, a temporary complete clinical remission or leukemia-free state was achieved. Our proof of concept real-time precision systems medicine study provides a paradigm for rapid tailoring of therapies for cancer patients in an era of exploding molecular information and emerging oncology drugs.