Chemotherapeutic agents circumvent emergence of dasatinib-resistant BCR-ABL kinase mutations in a precise mouse model of Philadelphia chromosome-positive acute lymphoblastic leukemia by Boulos Nidal, Mulder Heather L, Calabrese Christopher R, Morrison Jeffrey B, Rehg Jerold E, Relling Mary V, Sherr Charles J, Williams Richard T in Blood (2011). PubMed

Abstract

Introduction of cultured p185(BCR-ABL)-expressing (p185(+)) Arf(-/-) pre-B cells into healthy syngeneic mice induces aggressive acute lymphoblastic leukemia (ALL) that genetically and phenotypically mimics the human disease. We adapted this high-throughput Ph+ ALL animal model for in vivo luminescent imaging to investigate disease progression, targeted therapeutic response, and ALL relapse in living mice. Mice bearing high leukemic burdens (simulating human Ph+ ALLs at diagnosis) entered remission on maximally intensive, twice-daily dasatinib therapy but invariably relapsed with disseminated and/or central nervous system disease. Although relapse was frequently accompanied by the eventual appearance of leukemic clones harboring BCR-ABL kinase domain (KD) mutations that confer drug resistance, their clonal emergence required prolonged dasatinib exposure. KD P-loop mutations predominated in mice receiving less intensive therapy, whereas high dose treatment selected for T315I "gateway" mutations resistant to all three FDA-approved BCR-ABL kinase inhibitors. Addition of dexamethasone and/or L-asparaginase to reduced-intensity dasatinib therapy improved long-term survival of the majority of mice that received all three drugs. Although non-tumor cell-autonomous mechanisms can prevent full eradication of dasatinib-refractory ALL in this clinically relevant model, emergence of resistance to BCR-ABL kinase inhibitors can be effectively circumvented by the addition of 'conventional' chemotherapeutic agents with alternate anti-leukemic mechanisms of action.

[ hide abstract ]

Discussed In Paper