Researchers have developed a new combination therapy that is providing promising results in overcoming the resistance of a substantial population of multiple myeloma patients.

"This research builds on our previous studies that showed exposing multiple myeloma and leukemia cells to Chk1 inhibitors activated a protective response through the Ras/MEK/ERK signaling pathway," says Pei, instructor in the Department of Internal Medicine at the VCU School of Medicine. "By combining a Chk1 inhibitor with a MEK inhibitor, we have developed one of only a limited number of strategies shown to circumvent therapeutic resistance caused by high expressions of Mcl-1."
In laboratory experiments, the scientists enforced overexpression of Mcl-1 in human multiple myeloma cells. They found that this caused the cells to become highly resistant to bortezomib, but it failed to protect them from the Chk1/MEK inhibitor regimen. Additionally, the combination therapy was able to completely overcome resistance due to microenvironmental factors associated with increased expression of Mcl-1. A cell's microenvironment consists of surrounding cells and the fluids in which they reside, and the communication between cancer cells and their surrounding cells can significantly impact resistance. Mcl-1 plays a key role in this communication by facilitating events that promote cancer cell survival.
"Not only was the combination therapy effective against multiple myeloma cells, it notably did not harm normal bone marrow cells, raising the possibility of therapeutic selectivity," says Grant, the study's lead investigator and Shirley Carter Olsson and Sture Gordon Olsson Chair in Cancer Research, associate director for translational research and program co-leader of Developmental Therapeutics at VCU Massey Cancer Center. "We are hopeful that this research will lead to better therapies for multiple myeloma, and help make current therapies more effective by overcoming resistance caused by Mcl-1."
The researchers have started initial discussions with clinical investigators and drug manufacturers with hopes of developing a clinical trial testing a combination of Chk1 and MEK inhibitors in patients with refractory multiple myeloma. It is too early to estimate when the trial will open.
Source-Eurekalert