Combining Ibrance with drugs that inhibit the PI3K pathway was found to stop the growth of malignant pleural mesothelioma (MPM) cells more effectively than treatment with Ibrance alone.
Findings from the study, “Combined Inhibition of CDK4/6 and PI3K/AKT/mTOR Pathways Induces a Synergistic Anti-Tumor Effect in Malignant Pleural Mesothelioma Cells,” were published in the journal Neoplasia.
Unlike many other cancers, a mutation that clearly drives mesothelioma progression is still unknown. Instead, many of the genetic lesions found in this cancer type are those that lead to the loss of a tumor suppressor gene.
Tumor suppressor genes are those that impair cancer development, as is the case of DNA repair genes or genes that tightly control cell division, and thus cancer cells often get rid of them to proliferate.
The most frequently altered tumor suppressor in MPM is CDKN2A/ARF, a gene that encodes for two proteins called p16INK4a and p14ARF. These proteins are part of a cellular checkpoint that ensures a cell is fit to enter the cell cycle — in other words, to start proliferating.
If the checkpoint proteins find that a cell is unfit to proliferate, for example because it has too many mutations in its DNA, they make sure the cell does not start dividing until the problem is solved.
During the division process, there are several other checkpoints, making the cell proliferation a tightly regulated process. But in cancer cells, these checkpoint proteins are often mutated, which allows them to proliferate, even when they shouldn’t.
One of the major checkpoints in the cell division process involves the tumor suppressor retinoblastoma (Rb) protein, which controls the entry point into the cell cycle. For cells to begin synthesizing new DNA, Rb must be inhibited by a complex of proteins that include the cyclin D1 and the CDK4/6 proteins.
Ibrance is an orally available inhibitor of CDK4/6 which prevents cells from proliferating by keeping Rb intact. It is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic breast cancer.
Like many targeted therapies, Ibrance comes with side effects. One of them involves the activation of a pro-survival, pro-tumoral pathway called the PI3K/AKT/mTOR pathway.
“The PI3K/AKT/mTOR pathway plays a critical role in the control of cell growth, proliferation, metabolism, and migration, and is frequently deregulated in cancer cells, thus representing an attractive candidate for targeted cancer agents,” the researchers wrote.
For this reason, they evaluated how the combination of Ibrance with PI3K inhibitors would affect cell proliferation and cell death in MPM cells.
They used two different PI3K inhibitors: dactolisib (NVP-BEZ235) and alpelisib (NVP-BYL719), and tested the combination in a panel of MPM cell lines as well as on primary cell cultures derived from the pleural effusion of two MPM patients. Pleural effusion is an excess fluid that often accumulates between the thin membranes surrounding the lungs in mesothelioma patients.
All the cell models were sensitive to Ibrance and stopped dividing after 24 hours of treatment.
But when cells were treated with Ibrance followed by either dactolisib or alpelisib, the combination was significantly more effective than Ibrance alone. Indeed, whereas Ibrance only halted cell division but caused very little cell death, the combination could significantly increase cell death by as much as 16 percent.
These results were confirmed in 3D culture systems, which are more realistic cultures in which cells are suspended in media and grow as spheres.
The researchers then found that while after only one round of the combo treatment, cells were able to recover and start growing normally, after two cycles, the cells that were not killed stopped dividing irrevesibly.
This means that even if the combination therapy does not eliminate all cancer cells, the ones that remain are no longer able to proliferate, suggesting that cancer growth would stop altogether.
This work provides a novel therapeutic option for MPM patients. As the authors stated, “our results demonstrate that the association of [Ibrance] with PI3K inhibitors may represent a valuable new therapeutic approach for MPM treatment.”
