Cancer is a condition that is caused by mutation in genes. These altered genes in cancer can be divided into two primary categories: tumor suppressors and oncogenes. If a tumor suppressor gene is mutated, it can result in uncontrolled tumor growth, like having a vehicle without brakes. On the other hand, mutations in oncogenes can stimulate excessive cell growth, acting like a accelerator pedal that is pushed to the maximum.
Scientists who study mutations in tumor suppressor genes have particularly concentrated on p53, which is the most commonly mutated tumor suppressor gene in human cancers. Over the past 20 years, a lot of efforts have been made to create biologically specific treatments that trigger p53.
Despite the fact that studies have demonstrated that these therapies are successful in activating p53, they generally fail to eliminate cancer cells. Similar to other biologically targeted therapies, activation of p53 has been found to temporarily halt tumor growth, but the cells eventually develop mutations that make them resistant to treatment.
A recent study by scientists at the University of Colorado Cancer Center sheds light on the underlying mechanisms that prevent p53 activation from leading to effective cancer cell death. The study reveals that by blocking two specific suppressors of p53, cancer cell death can be induced through the activation of a related gene network called the Integrated Stress Response.
“When you block both the major p53 repressor, known as MDM2, and its minor repressor, known as PPM1D, p53 works much better in terms of inducing cancer cell death, and this enhanced killing activity requires the Integrated Stress Response” explains Joaquin Espinosa, PhD, a professor of pharmacology in the CU School of Medicine, director of the Linda Crnic Institute for Down syndrome, and senior author of the study. “This is an important step in making p53-based biologically targeted therapies more effective.”
This research outcome marks a crucial moment in the nearly 20 years of research led by Zdenek Andrysik, PhD, an assistant research professor of pharmacology at the CU School of Medicine, and other members of the Espinosa laboratory. Their research, along with other studies, has aimed to uncover the function of MDM2 and PPM1D, the two proteins that suppress p53 within tumor cells, and how inhibiting them results in cancer cell death.
“It was already established that MDM2 is a major repressor and PPM1D is a minor one,” Espinosa explains. “For a long time, the hope was that inhibiting just the major repressor would suffice. Much effort was invested in developing small molecules that block MDM2, millions of dollars were spent, but these drugs performed poorly in clinical trials.”
The researchers then focused on secondary repressors, including PPM1D. “Much less is known about PPM1D and other minor p53 repressors,” says Andrysik. “However, it was soon evident that inhibiting both MDM2 and PPM1D would allow p53 to effectively cause cancer cell death. Nevertheless, the mechanisms driving this cooperative effect were unclear.”
Espinosa and Andrysik have demonstrated that the inhibition of MDM2 and PPM1D activates the Integrated Stress Response, which then triggers the production of a protein called ATF4. They also showed that when ATF4 partners with p53, it works together to cause cancer cell death.
According to Andrysik, this mechanism of inhibiting MDM2 and PPM1D, which allows p53 to work with ATF4 in killing cancer cells, has shown potential for multiple types of cancer in the lab. This newfound understanding has also opened up new avenues for pharmacological strategies to trigger cancer cell death.
For instance, Andrysik and Espinosa repurposed a drug called Nelfinavir, which was originally approved as an HIV therapy.
Espinosa says, “We now know that Nelfinavir activates the Integrated Stress Response, making it a great candidate to combine with MDM2 inhibitors.”
Andrysik and Espinosa are further exploring the synergistic impact that results when both MDM2 and PPM1D are suppressed and p53 is activated. According to Andrysik, the research suggests that cancer cells are particularly sensitive to this dual activation of p53 and the Integrated Stress Response, providing a therapeutic opportunity that may spare normal cells from being impacted.
Espinosa says that for decades, the goal of cancer research has been to revive the activity of p53, causing tumor regression. With the increasing understanding of mutated genes and proteins in cancer, researchers are better equipped to identify when the brakes are failing or the gas pedal is all the way down, and restore them using targeted inhibitors.