Triple-combination therapy prevents drug resistance in colorectal cancer cells

After finding that triple-combination therapy may help to prevent resistance acquisition in colorectal cancer cells, the researchers said that future studies should look into questions of timing, dosage and tolerability.

Colon cancer micrograph

Treating colorectal cancer with a trio of targeted drugs reduces the acquisition of drug resistance, in vitro research published in Oncogene shows (25 March 2019)[1]
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Researchers treated a panel of 47 human colorectal cancer cell lines with combinations of MEK- PI3K- and ERK-inhibitors. These signalling pathways are frequently activated in colorectal tumours.

They found that treating cells with a MEK-PI3K-inhibitor combination led to a synergistic effect in cell growth inhibition. Cells that acquired resistance could be successfully treated with an ERK-PI3K regimen, but subsequently developed resistance to this treatment regimen too.

However, adding a low concentration of navitoclax, a BCL2-family inhibitor, to the MEK-PI3K regimen in previously untreated cells resulted in improved synergistic interaction between the therapies and blocked the acquisition of resistance.

The researchers said the findings indicated that triple-combination therapy may help to prevent resistance acquisition, rather than overcoming pre-existing resistance. Future studies should look into the questions of timing, dosage and tolerability, they added.

“It is possible that the addition of a third agent may be tolerated clinically in such a dosing regimen and provide the opportunity to overcome, or ameliorate, the major clinical problem of resistance to targeted therapies,” they concluded.

References

[1] Clarke P, Roe T, Swabey K et al. Dissecting mechanisms of resistance to targeted drug combination therapy in human colorectal cancer. Oncogene 2019; In press. doi: 10.1038/s41388-019-0780-z

Last updated
Citation
Clinical Pharmacist, CP, May 2019, Vol 11, No 5;11(5):DOI:10.1211/PJ.2019.20206504