Overcoming Resistance in Patient-Derived Xenograft Models of BCR-ABL-Rearranged Acute Lymphoblastic Leukemia

Abstract

The BCR-ABL fusion oncogene defines the most common molecular subtype of acute lymphoblastic leukemia in adults (BCR-ABL+ ALL) and has historically conferred an adverse prognosis. Incorporation of tyrosine kinase inhibitors (TKIs) that bind the ABL kinase domain into frontline regimens induces complete remissions in greater than 90% of patients, but most relapse with resistance mutations in ABL that disfavor drug binding. This suggests that relapses after TKI therapy remain addicted to ABL kinase activity. In contrast to currently approved TKIs, type IV inhibitors bind the spatially distinct myristate site in the ABL kinase domain and allosterically modulate BCR-ABL function. We hypothesize that the combination of catalytic and allosteric inhibitors can prevent the emergence of cross-resistant clones and cure some BCR-ABL+ ALLs. If this hypothesis proves correct, it would revolutionize the treatment of BCR-ABL+ ALL. Even in cases where combined ABL blockade is not curative, we would have the unique opportunity to define mechanisms of in vivo resistance – mutational, transcriptional, or differentiation state-mediated – to what is potentially the future standard therapy for BCR-ABL+ ALL. The studies described herein all relate to our overarching goal of informing curative therapeutic strategies for BCR-ABL ALL by defining the factors that modulate sensitivity and resistance to targeted ABL inhibition.