Gene mutations are the cause of cancer. Tumor suppressors and oncogenes are the two main groups of these altered genes in cancer. Mutations in oncogenes can drive cell proliferation, pushing the gas pedal to the floor, whereas mutations in tumor suppressor genes can cause tumors to grow unchecked—a situation in which there is no control.
P53, the tumor suppressor gene that is most often mutated in human cancers, has received considerable attention from researchers researching tumor suppressor gene alterations. Designing biologically focused therapeutics that precisely activate p53 has taken up a lot of time and energy over the past two decades.
Even while studies have demonstrated that these treatments can stimulate p53 activity, they often are unable to eradicate cancer cells. Activation of p53 has been proven to temporarily halt tumor growth, as has been shown with other biologically targeted treatments, but over time, the tumor cells change and develop resistance to the treatment.
The mechanisms that inhibit p53 activation from effectively causing cancer cell death are now better understood according to recent research from the University of Colorado Cancer Center. They demonstrate that blocking two different p53 repressors can cause cancer cell death by activating an additional 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. This is an important step in making p53-based biologically targeted therapies more effective.”
Joaquin Espinosa, PhD, Study Senior Author, Professor, Pharmacology, School of Medicine, University of Colorado School of Medicine
Espinosa is also the director of the Linda Crnic Institute for Down Syndrome.
Inducing cancer cell death
Zdenek Andrysik, PhD, Assistant Research Professor of Pharmacology at the CU School of Medicine, together with other members of the Espinosa lab, have been working on this idea for almost two decades. It represents a significant turning point in their work.
Their study and that of others have aimed to comprehend the function of MDM2 and PPM1D, two proteins that suppress p53 inside tumor cells, and the processes by which their inhibition results in the death of cancer cells.
Espinosa added, “It was already established that MDM2 is a major repressor and PPM1D is a minor one. 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 focus of research shifted to lesser repressors, such as PPM1D.
A lot less is known about PPM1D and other minor repressors of p53, but it soon became clear that if you inhibit both MDM2 and PPM1D, p53 can effectively induce cancer cell death. However, the underlying mechanisms driving this synergy were unknown.”
Zdenek Andrysik, PhD, Assistant Research Professor, Pharmacology, University of Colorado School of Medicine
Understanding the mechanisms
Espinosa and Andrysik have shown that the Integrated Stress Response, a signaling pathway that boosts the protein ATF4, is activated when MDM2 and PPM1D are inhibited. Additionally, they revealed how ATF4 and p53 collaborate to kill cancer cells.
Multiple cancer types have shown promise in the lab when MDM2 and PPM1D are inhibited, allowing p53 to work with ATF4 to put cancer cells to death. Additional pharmacological techniques to cause cancer cell death was rapidly discovered as a result of this mechanistic understanding.
For instance, Nelfinavir, a medicine that was first authorized as an HIV therapy, was repurposed by Andrysik and Espinosa.
“Now we know that Nelfinavir activates the Integrated Stress Response, thus becoming a great combination with MDM2 inhibitors,” Espinosa added.
As p53 is activated, MDM2 and PPM1D are suppressed, and a synergistic response occurs. Andrysik and Espinosa are continuing their study to learn more about the mechanisms of this synergistic response.
Andrysik further added, “Our data indicates that cancer cells are particularly vulnerable to this dual activation of p53 and the Integrated Stress Response, which may offer a therapeutic window in the clinic, sparing normal cells from the killing effects of p53.”
Espinosa stated, “A holy grail of cancer research has been the restoration of p53 activity to induce tumor regression. For the past 20, 30 years, a lot of research efforts have been devoted to finding more elegant solutions to broadly acting chemotherapy or radiation.”
He concluded, “As we learn more about the genes and proteins mutated in cancer, we’re more able to see when the brakes are failing and restore them, or when the gas pedal is all the way to the floor and lift it with specifically targeted inhibitors.”
Andrysik, Z., et al. (2023). PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response. Nature Communications. doi.org10.1038/s41467-022-35089-5