Cancer is a disease driven by gene mutations. These mutated genes in cancer fall into two major categories: tumor suppressors and oncogenes. Mutations in tumor suppressor genes can allow tumors to grow unchecked – a case of no brakes – while mutations in oncogenes can activate cell proliferation, pushing the gas pedal all of the solution to the ground.

Researchers studying mutations in tumor suppressor genes have dedicated significant focus to p53, essentially the most continuously mutated tumor suppressor gene in human cancers. Over the past twenty years, much effort has been dedicated to designing biologically targeted therapies that specifically activate p53.

Nonetheless, while research has shown that these therapies are effective at inducing p53 activity, they typically cannot kill cancer cells. As observed for other biologically targeted therapies, activation of p53 has been shown to stop tumor growth for a time period, however the cells eventually mutate and turn into proof against treatment.

Recent research by University of Colorado Cancer Center scientists illuminates the mechanisms at work that prevent p53 activation from triggering effective cancer cell death. They show that inhibiting two distinct repressors of p53 can elicit cancer cell death through activation of a complementary gene network referred to as the Integrated Stress Response.

Once you block each the most important p53 repressor, referred to as MDM2, and its minor repressor, referred to as PPM1D, p53 works a lot better when it comes to inducing cancer cell death, and this enhanced killing activity requires the Integrated Stress Response. That is a very important step in making p53-based biologically targeted therapies more practical.”

Joaquin Espinosa, PhD, professor of pharmacology within the CU School of Medicine, director of the Linda Crnic Institute for Down syndrome, and senior creator of the study

Inducing cancer cell death

This development is a very important milestone in almost twenty years of research conducted by Zdenek Andrysik, PhD, an assistant research professor of pharmacology within the CU School of Medicine, and other members of the Espinosa lab. Their and other research has worked to grasp the role of MDM2 and PPM1D, two proteins that repress p53 inside tumor cells, and the mechanisms by which inhibiting them results in cancer cell death.

“It was already established that MDM2 is a significant repressor and PPM1D is a minor one,” Espinosa explains. “For a very long time, the hope was that inhibiting just the most important repressor would suffice. Much effort was invested in developing small molecules that block MDM2, hundreds of thousands of dollars were spent, but these drugs performed poorly in clinical trials.”

Researchers then turned to minor repressors, including PPM1D. “So much less is understood about PPM1D and other minor repressors of p53,” Andrysik says, “however it soon became clear that in case you inhibit each MDM2 and PPM1D, p53 can effectively induce cancer cell death. Nonetheless, the underlying mechanisms driving this synergy were unknown”.

Understanding the mechanisms

Espinosa and Andrysik have been in a position to exhibit that inhibiting MDM2 and PPM1D prompts the Integrated Stress Response, which is a signaling pathway that stimulates a protein called ATF4. They further demonstrated that ATF4 partners with p53, working together to cause cancer cell death.

Inhibiting MDM2 and PPM1D, and thus allowing p53 to partner with ATF4 in taking cancer cells to death, has shown promise for multiple cancer types within the laboratory, Andrysik says. This mechanistic insight quickly revealed additional pharmacological strategies to induce cancer cell death.

For instance, Andrysik and Espinosa repurposed the drug Nelfinavir, which originally was approved as an HIV therapy. “Now we all know that Nelfinavir prompts the Integrated Stress Response, thus becoming an incredible combination with MDM2 inhibitors,” Espinosa says.

Andrysik and Espinosa are continuing their research to grasp more about mechanisms of the synergistic response that happens when MDM2 and PPM1D are inhibited and p53 is activated. “Our data indicates that cancer cells are particularly vulnerable to this dual activation of p53 and the Integrated Stress Response, which can offer a therapeutic window within the clinic, sparing normal cells from the killing effects of p53,” Andrysik says.

Espinosa adds that “a holy grail of cancer research has been the restoration of p53 activity to induce tumor regression. For the past 20, 30 years, quite a lot of research efforts have been dedicated to finding more elegant solutions to broadly acting chemotherapy or radiation. As we learn more concerning the genes and proteins mutated in cancer, we’re more in a position to see when the brakes are failing and restore them, or when the gas pedal is all of the solution to the ground and lift it with specifically targeted inhibitors.”

Source:

University of Colorado Anschutz

Journal reference:

Andrysik, Z., et al. (2022) PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response. Nature Communications. doi.org/10.1038/s41467-022-35089-5.