Scientists defeat hurdle to eradicating inactive multiple myeloma cells

November 14, 2011 By John Wallace

Researchers at Virginia Commonwealth University Massey Cancer Center have developed a novel treatment strategy for multiple myeloma that delivers a deadly one-two blow to kill even the most inactive, or cytokinetically quiescent, cells. Because multiple myeloma can rest in a non-proliferative state for extended periods of time, this discovery may help to overcome a major hurdle to treating this fatal disease.  

Recently published in the journal “Blood,” a study by a team of researchers led by Steven Grant, M.D., Shirley Carter Olsson and Sture Gordon Olsson Chair in Oncology Research, associate director for translational research and program co-leader of Developmental Therapeutics at VCU Massey Cancer Center, shows that combining the clinically relevant MEK1/2 inhibitor AZD6244 and the Chk1 inhibitor AZD7762 effectively induces apoptosis, a form of cell suicide, in actively cycling as well as quiescent cells. Chk1 prevent cells from arresting in stages of the that facilitate the repair of DNA damage. However, these agents may also interfere with multiple other Chk1-related survival functions. MEK1/2 inhibitors prevent cells from activating a variety of proteins responsible for promoting various DNA repair mechanisms, among numerous other actions. The combination of drugs did not appear to harm normal, healthy bone marrow tissue.

“We believe Chk1 inhibitors by themselves may not always be effective against multiple myeloma because they target the cell cycle process, but multiple myeloma cells are frequently not actively cycling,” says Grant. “Nevertheless, Chk1 inhibitors may still induce limited DNA injury in non-cycling cells, which have alternative ways to repair the damage. By introducing a MEK1/2 inhibitor, we may have disabled compensatory DNA repair pathways, thereby leaving cells, including those that are not cycling, with few options besides apoptosis.”

All cells progress through a cycle that leads to DNA replication and cell division. Each phase of the cycle is responsible for different biological functions. In the first phase, known as G0, cells rest after progressing through mitosis, the final phase of the cell cycle that separates a cell’s chromosomes in the nucleus into two daughter nuclei. Cells in the G0 phase and early G1 phase are in a regenerative state, repairing damage to their DNA. Chk1 inhibitors promote DNA damage by allowing cells to enter the cell cycle inappropriately, where they die. Historically, dormant cells such as multiple myeloma cells have been less susceptible to Chk1 inhibitor strategies, such as those that combine conventional DNA-damaging chemotherapies.

MEK1/2 inhibitors interfere with a signaling cascade known as the Ras/Raf/MEK/ERK pathway. This pathway, one of the most commonly dysregulated pathways in cancer, is comprised of a chain of cellular proteins  that act like on/off switches for a variety of biological processes mediating cell survival and cell cycle progression, among others. One important survival mechanism is responsible for regulating a pro-apoptotic protein known as Bim. By inhibiting the Ras/Raf/MEK/ERK pathway, MEK1/2 inhibitors allow Bim to accumulate in cells. This lowers the threshold for apoptosis in cells and appears to serve as a particularly effective “death trigger” that promotes elimination of containing DNA damage.

“A multi-institutional phase II clinical trial evaluating AZD6244 in patients with refractory multiple myeloma has recently been initiated. Since this agent is already being evaluated in a clinical setting, we are hoping this will accelerate the translational research process and our study will provide the foundation needed for successor trials combining this agent with clinically relevant Chk1 inhibitors like AZD7762,” says Grant.

The full research manuscript is available online here.

Explore further: Blocking molecular target could make more cancers treatable with PARP inhibitors

Related Stories

Blocking molecular target could make more cancers treatable with PARP inhibitors

June 29, 2011
BOSTON--Researchers at Dana-Farber Cancer Institute have demonstrated a molecular strategy they say could make a much larger variety of tumors treatable with PARP inhibitors, a promising new class of cancer drugs.

Breakthrough could make 'smart drugs' effective for many cancer patients

June 27, 2011
(Medical Xpress) -- Newcastle and Harvard University reseachers have found that blocking a key component of the DNA repair process could extend the use of a new range of 'smart' cancer drugs called PARP inhibitors.

Recommended for you

Study may explain failure of retinoic acid trials against breast cancer

July 25, 2017
Estrogen-positive breast cancers are often treated with anti-estrogen therapies. But about half of these cancers contain a subpopulation of cells marked by the protein cytokeratin 5 (CK5), which resists treatment—and breast ...

Physical activity could combat fatigue, cognitive decline in cancer survivors

July 25, 2017
A new study indicates that cancer patients and survivors have a ready weapon against fatigue and "chemo brain": a brisk walk.

Breaking the genetic resistance of lung cancer and melanoma

July 25, 2017
Researchers from Monash University and the Memorial Sloan Kettering Cancer Center (MSKCC, New York) have discovered why some cancers – particularly lung cancer and melanoma – are able to quickly develop deadly resistance ...

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Immune cells the missing ingredient in new bladder cancer treatment

July 24, 2017
New research offers a possible explanation for why a new type of cancer treatment hasn't been working as expected against bladder cancer.

Anti-cancer chemotherapeutic agent inhibits glioblastoma growth and radiation resistance

July 24, 2017
Glioblastoma is a primary brain tumor with dismal survival rates, even after treatment with surgery, chemotherapy and radiation. A small subpopulation of tumor cells—glioma stem cells—is responsible for glioblastoma's ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.