More info on new drug

[Guest guest]

This is interesting as the drug is not even in clinical trials yet cell

screening strategies are already being studied for a possible combinatory

strategy with IM.

Happy reading!

Cheers,

Cheryl-Anne

A cell-based screen for resistance of Bcr-Abl-positive leukemia identifies

the mutation pattern for PD166326, an alternative Abl kinase inhibitor.

von Bubnoff N, Veach DR, van der Kuip H, Aulitzky WE, Sanger J, Seipel P,

Bornmann WG, Peschel C, son B, Duyster J.

Department of Internal Medicine III, Technical University of Munich, D-81675

Munich, Germany.

In Philadelphia-positive (Ph(+)) leukemia, point mutations within the

Bcr-Abl kinase domain emerged as a major mechanism of resistance to imatinib

mesylate. We established a cell-based screening strategy for detection of

clinically relevant point mutations using Bcr-Abl-transformed Ba/F3 cells.

We identified 32 different single-point mutations within the kinase domain

of Bcr-Abl. The pattern and frequency of mutations in this cell

culture-based screen resembled the pattern and frequency observed in

resistant patients. We then applied this screen to an alternative Abl kinase

inhibitor. Using PD166326, the frequency of resistant colonies emerging at 5

to 10 times the median growth inhibition (IC50) of PD166326 was

significantly lower than with imatinib. In addition, PD166326 produced a

distinct pattern of Bcr-Abl mutations. The majority of mutations that came

up with both imatinib and PD166326 could effectively be suppressed by

increasing the dose of PD166326 to 50 to 500 nM. In contrast, only a few

mutations could be suppressed by increasing the imatinib dose to 5 to 10

microM. However, 3 mutations affecting F317 displayed complete resistance to

PD166326, but could be effectively inhibited by standard concentrations of

imatinib. Thus, this robust and simple screening system provides a rational

basis for combinatorial and sequential treatment strategies in targeted

cancer therapy.