New approach to overcoming TKI resistance
Published: 18/05/2011 19:16:51
by ecancer reporter Janet Fricker
US researchers have developed a new approach to overcoming drug resistance in patients with leukaemia treated with tyrosine kinase inhibitors (TKIs), reports the journal Nature.
TKIs are widely used to treat patients with leukaemia driven by BCR -ABL, such as Chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL). After initially successful treatments it is well known that TKIs can fail to work due to patients developing resistance to treatment.
In the current study Markus M?schen and colleagues, from the University of California at San Francisco (CA, USA), report on the discovery that TKIs are able to activate a BCL6-dependent mechanism of drug resistance. The investigators showed that TKI induced upregulation of BCL6 messenger RNA levels that could be confirmed in multiple leukaemia subtypes carrying oncogenic tyrosine kinases. BCL6 is a repressor that is required for the survival of mature B cells and T follicular helper cells. The investigators found that upregulation of BCL6 production as a result of TKI treatment enabled the survival of leukemic cells that undergo rapid death in the absence of BCL6.
The investigators were then able to go on to show that targeted inhibition of BCL6 with a novel BCL6 peptide inhibitor in mice that had been engrafted with patient derived BCR-ABL reduced the number of drug resistant and self -renewing leukaemia initiating cells.
Adopting a dual targeting strategy of oncogenic tyrosine kinases and BCL6-dependent feedback, the authors suggest, would offer a novel strategy to eradicate drug-resistant and leukaemia-initiating subclones in tyrosine-kinase driven leukaemia.
"Although transcription factors have been considered intractable therapeutic targets, the recent development of a small molecule inhibitor against BCL6 holds promise for effectively targeting TKI-resistance in patients with Ph+ ALL. Because TKI-resistance develops in virtually all cases of Ph+ ALL, it appears particularly important to target this novel pathway of TKI resistance," write the authors.
Article: Duy C, Hurtz C, Shojaee S, et al BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition. Nature 2011. Doi: 10.1038/nature09883.