A new study helps explain why some chronic myeloid leukemia (CML) patients develop resistance to imatinib despite the absence of BCR-ABL mutations.
Researchers discovered that a signaling pathway associated with cell division and growth acts as an alternative survival signal underlying imatinib resistance.
But blocking this pathway with an inhibitor known as trametinib can prevent resistance to imatinib and increase survival in mice.
The researchers recounted these discoveries in Science Translational Medicine.
Michael R. Green, MD, PhD, of the University of Massachusetts Medical School in Worcester, and his colleagues began this research with a large-scale RNA interference screen. This revealed a set of genes that promote imatinib sensitivity.
The team then set out to identify the regulatory pathways through which these genes promote imatinib sensitivity. They found that knocking down the genes in BCR-ABL+ cells results in sustained RAF/MEK/ERK signaling after treatment with imatinib.
Further investigation revealed it is PRKCH, which encodes the protein kinase C family member PKCĪ·, that increases RAF/MEK/ERK signaling through phosphorylation and activation of CRAF.
Dr Green and his colleagues also found that PRKCH is upregulated in CML cell lines and patient samples that exhibit BCR-ABL-independent imatinib resistance. Experiments in mice revealed that PRKCH modulates the proliferation of BCR-ABL+ cells, CML progression, and imatinib sensitivity.
Furthermore, imatinib-resistant murine and human CML stem cells contained high levels of PRKCH. And experiments confirmed that high PRKCH expression contributed to the imatinib resistance observed in these cells.
Fortunately, the researchers discovered that combining imatinib with the MEK inhibitor trametinib can overcome BCR-ABL-independent imatinib resistance in CML cells. The combination also prolonged survival in mouse models of imatinib-resistant CML.
Dr Green and his colleagues said these results reveal a mechanism of BCR-ABL-independent imatinib resistance that can be targeted with therapy. And, as treatment with trametinib and imatinib kills CML stem cells but spares normal hematopoietic stem cells, it may be a feasible treatment option for CML patients.
