Inhibition of Oncogene PAK4 Overcomes Resistance to PD-1 Immunotherapy

Inhibition of Oncogene PAK4 Overcomes Resistance to PD-1 Immunotherapy

Immunotherapy can be an effective treatment for some cancer patients. The treatment involves harnessing the body’s immune system and using it to attack cancer cells that would otherwise be treated as benign.

One of the leading forms of cancer immunotherapy is PD-1 blockade. PD-1 is a protein – programmed cell death protein 1 – on the surface of cells that down regulates the immune response, suppresses T-cell inflammatory activity, and crucially, can stop the immune system from killing cancer cells.

PD-1 blockade, as the name suggests, blocks that protein’s activity and by doing so the immune system attacks the cancer cells. However, in some patients PD-1 blockade is ineffective and they are resistant to the drug.

New research conducted at the UCLA Jonsson Comprehensive Cancer Center has provided clues as to why that is the case, which could lead to treatments that would eradicate resistance to PD-1 blockade therapy.

The researchers analyzed biopsies of patients with advanced melanoma who had received immunotherapy with pembrolizumab. RNA sequencing determined the phenotype of the tumors, and those that did not respond to PD-1 blockade displayed overexpression of the oncogene PAK4, which led the researchers to believe that PAK4 played a role in resistance to PD-1 blockade immunotherapy.

It was previously understood that PAK4 played a role in cell migration and proliferation. The new research showed that high expression of PAK4 correlates with poor migration of T-cells to tumors and stops them from attacking and killing cancer cells.

The team then used CRISPR-Cas9 and drug inhibitors to remove or inhibit PAK4 in cell lines and discovered that when PAK4 was inhibited or deleted there was increased migration of tumor-specific immune cells to the tumor cells. The tumors became sensitized to PD-1 blockade immunotherapy.

Combining a PAK4 inhibitor with PD-1 blockade immunotherapy could improve the effectiveness of the treatment and make effective in a much wider group of patients. Currently, the PAK4 inhibitor tested by the researchers is being tested in a phase 1 clinical trial. The researchers expect to test the new combination therapy in patients in the near future.

“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,” said Dr. Antoni Ribas, senior author of the study.

The research is detailed in the paper – PAK4 inhibition improves PD-1 blockade immunotherapy – which was recently published in the journal Nature Cancer. DOI: 10.1038/s43018-019-0003-0

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