Imatinib Mesylate Resistance Through BCR-ABL Independence in Chronic Myelogenous Leukemia

Abstract

Imatinib mesylate (IM) binds to the BCR-ABL protein, inhibiting its kinase activity and effectively controlling diseases driven by this kinase. IM resistance has been associated with kinase mutations or increased BCR-ABL expression. However, disease progression may be mediated by other mechanisms that render tumor cells independent of BCR-ABL. To demonstrate this potential, IM-resistant cells were found in chronic myelogenous leukemia patients with continuous BCR-ABL gene expression but undetectable BCR-ABL protein expression. These cells were unresponsive to IM and acquired BCR-ABL-independent signaling characteristics. IM resistance in some patients may be mediated through loss of kinase target dependence.

Synergistic interactions between MEK1/2 and histone deacetylase inhibitors in BCR/ABL+ human leukemia cells

“…The Bcr/Abl kinase activates multiple downstream cytoprotective signaling cascades, including those related to PI3K/Akt, Stat, NF-kB, and ERK, among others. [2][3][4]6 In this regard, ERK activation has been specifically linked to the prosurvival activities of Bcr/Abl in CML cells. 21 Moreover, the net balance between proapoptotic signaling pathways such as ERK and stress-related cascades (eg JNK) is known to be a critical determinant of cell fate.…”

“…1 This mutant gene encodes the constitutively active Bcr/Abl kinase, which signals downstream to a variety of cytoprotective pathways including extracellular signal-regulated kinase (ERK), Akt, NF-kB, Jak/ STAT, and Bcl-x L , among others. [2][3][4] Collectively, activation of these pathways confers a survival advantage on Bcr/Abl þ cells, and is responsible for leukemic transformation. 5 In addition to promoting leukemic cell survival, the Bcr/Abl kinase renders cells resistant to a wide range of conventional cytotoxic drugs active in leukemia.…”

Identification of genes involved in imatinib resistance in CML: a gene-expression profiling approach

“…Our results suggest that largely BCR-ABLindependent mechanisms are potentially related to primary imatinib resistance in CML patients. 11,17 …”

“…Other resistance mechanisms have been demonstrated, such as src-kinase LYN overexpression, 10 or proposed, like constitutive nuclear factor (NF)-kB activation. 11,12 Taking into account the diversity of the mechanisms involved in imatinib resistance, we employed expression profiling to identify genes that may be involved in this resistance, as determined by cytogenetic and molecular responses. These results also provide insight into the mechanisms leading to this resistance.…”

Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate

“…2,3 However, a subset of patients eventually develop resistance, particularly those treated in the advanced stages. 4,5 Both BCR-ABL-dependent [4][5][6][7] and -independent [8][9][10] mechanisms of resistance have been described. Point mutations of the Abl kinase domain appear to be the most common, occurring in 30-90% of patients who develop resistance.…”