De_novo_and_acquired_resistance_to_MEK_inhibitors_
Aim: To investigate de novo and acquired resistance to MEK inhibitors and the relative fitness of parental and MEK-resistant clones in AMLs characterized by Nf1 inactivation or by oncogenic Nras/Kras expression. Rationale: We have recently extended the paradigm developed in Nf1 mutant AML to interrogate response, clonal evolution, and relapse in leukemias with oncogenic Nras/Kras mutations. We will incorporate next generation sequencing and expression profiling to enhance our understanding of sensitivity and resistance to MEK inhibition and will directly compare the fitness of sensitive parental and resistant AMLs that emerge during treatment with targeted agents.