Environment-mediated drug resistance in Bcr/Abl-positive acute lymphoblastic leukemia

Abstract

Although cure rates for acute lymphoblastic leukemia (ALL) have increased, development of resistance to drugs and patient relapse are common. The environment in which the leukemia cells are present during the drug treatment is known to provide significant survival benefit. Here, we have modeled this process by culturing murine Bcr/Abl-positive acute lymphoblastic leukemia cells in the presence of stroma while treating them with a moderate dose of two unrelated drugs, the farnesyltransferase inhibitor lonafarnib and the tyrosine kinase inhibitor nilotinib. This results in an initial large reduction in cell viability of the culture and inhibition of cell proliferation. However, after a number of days, cell death ceases and the culture becomes drug-tolerant, enabling cell division to resume. Using gene expression profiling, we found that the development of drug resistance was accompanied by massive transcriptional upregulation of genes that are associated with general inflammatory responses such as the metalloproteinase MMP9. MMP9 protein levels and enzymatic activity were also increased in ALL cells that had become nilotinib-tolerant. Activation of p38, Akt and Erk correlated with the development of environment-mediated drug resistance (EMDR), and inhibitors of Akt and Erk in combination with nilotinib reduced the ability of the cells to develop resistance. However, inhibition of p38 promoted increased resistance to nilotinib. We conclude that development of EMDR by ALL cells involves changes in numerous intracellular pathways. Development of tolerance to drugs such as nilotinib may therefore be circumvented by simultaneous treatment with other drugs having divergent targets.

Selective Akt Inhibitors Synergize with Tyrosine Kinase Inhibitors and Effectively Override Stroma-Associated Cytoprotection of Mutant FLT3-Positive AML Cells

“…Inhibitors of Akt and Erk combined respectively with nilotinib diminished resistance. In contrast to our findings, however, inhibition of p38 MAPK in this study increased TKI (nilotinib) resistance [29].…”

Tumor-Associated Macrophages in SHH Subgroup of Medulloblastomas

“…The tumor microenvironment also plays an important role in drug resistance mechanisms of tumors. Coculture of leukemia cells with stromal cells allows for environment-mediated drug resistance (EMDR) to tyrosine kinase inhibitors (42). This EMDR is associated with differential regulation of inflammation-related genes.…”

Galectin-3 in pre-B acute lymphoblastic leukemia

“…Microarray analysis on precursor B-lineage (pre-B) ALL cells from a BCR/ABL transgenic mouse model for Ph-positive ALL undergoing environmental-mediated drug resistance showed significantly increased expression of mRNAs related to stress and inflammation. 6 Among others, we found that transcript levels of the Galectin-3 gene ( Lgals3 ) were significantly increased upon development of resistance to the Bcr/Abl-targeted tyrosine kinase inhibitor nilotinib, and this was also seen in pre-B ALL cells isolated from the BM of BCR/ABL transgenic mice that had been treated with nilotinib for 8 days. 6 …”

“…6 Among others, we found that transcript levels of the Galectin-3 gene ( Lgals3 ) were significantly increased upon development of resistance to the Bcr/Abl-targeted tyrosine kinase inhibitor nilotinib, and this was also seen in pre-B ALL cells isolated from the BM of BCR/ABL transgenic mice that had been treated with nilotinib for 8 days. 6 …”