PAK4 Inhibition Reverses Immunotherapy Resistance

Cancer immunotherapy drugs, which harness the body’s immune system to attack cancer cells, have significantly changed the face of cancer treatment. People with aggressive cancers are now living longer, healthier lives. Unfortunately, cancer immunotherapy only works in a subset of patients.

A new UCLA study helps explain why some people with advanced cancer may not respond to one of the leading immunotherapies (PD-1 blockade) and how a new combination approach may help overcome resistance to the immunotherapy drug. The study, published today in Nature Cancer, showed that genetic and pharmacological inhibition of the oncogene PAK4 overcomes resistance to anti-PD-1 therapy in preclinical models.

“One of the main reasons patients do not respond to PD-1 blockade is because the T cells never make it into the tumor to attack the cancer cells,” says lead author Gabriel Abril-Rodriguez. “We found that biopsies of patients who did not respond to PD-1 blockade showed an overexpression of PAK4, so that led us to believe it played a role in suppressing the immunotherapy treatment.”

PAK4 has been known previously to be involved in cell migration and proliferation. The new research from UCLA demonstrates that high expression of this oncogene also correlates with a lack of immune cells migrating into the tumors to destroy the cancer cells.

Using biopsies from people with advanced melanoma who received the immune checkpoint-blocking antibody pembrolizumab, the researchers performed RNA sequencing to characterize the phenotype of the tumors. They found that the tumors that did not respond to PD-1 blockade had a high expression of PAK4 and were not infiltrated by immune cells. But when PAK4 was deleted, the migration of tumor-specific immune cells was increased, sensitizing tumors to PD-1 blockade immunotherapy.

“Developing new and improved combination treatments like this one for people who do not initially respond to anti-PD-1 treatment is the next step forward in our efforts to make immunotherapy work better for more people,” says senior author Antoni Ribas. “The results from this study could also be expanded to other tumor types that are notoriously resistant to PD-1 blockade, such as pancreatic cancer.”

The PAK4 inhibitor used in the study is already being tested in a phase-one trial. The combination treatment with anti-PD-1 will be tested in a clinical trial setting in the near future.