PAK4 inhibitor, a new assistant of PD-1

Wen man dialect The success of immunotherapy such as PD-1 antibody has significantly changed the current situation of cancer treatment This new therapy, which regulates the human immune system to attack cancer cells, gives patients with invasive cancer a chance to live longer and healthier Unfortunately, at present, cancer immunotherapy is only effective for a small number of patients In a new study published in nature cancer on December 9, scientists from the University of California, Los Angeles (UCLA) explained why some patients with advanced cancer do not respond to PD-1 antibodies, and how a new combination therapy can help overcome patients' resistance to this immunotherapy drug Specifically, the researchers first sequenced the RNA from the biopsy tissues of patients with advanced melanoma who received PD-1 antibody treatment The results showed that the oncogene PAK4 (full name p21-activated kinase 4) was highly expressed in the tumors that did not respond to PD-1 blocking, and there was a lack of infiltration of immune cells (T cells and dendritic cells) One of the main reasons that patients do not respond to PD-1 blockade is that T cells fail to enter the tumor to attack the cancer cells Tissue biopsies of patients who did not respond to the PD-1 antibody showed an overexpression of PAK4, suggesting that the protein may play a role in immunosuppressive therapy " Gabriel Abril Rodriguez, who participated in the study, explained Next, scientists used the PAK4 inhibitor kpt-9274 or gene editing technology CRISPR to inhibit the role of PAK4 in cancer cells The results showed that deletion of PAK4 gene increased T cell infiltration and reversed PD-1 blocking drug resistance in a cd8-t cell-dependent manner In addition, compared with PD-1 single drug therapy, kpt-9274, an inhibitor of PAK4, combined with PD-1 antibody, effectively improved anti-tumor response In conclusion, this study confirmed that the high expression of PAK4, a previously known carcinogenic gene related to cell migration and proliferation, is also related to the migration of immunodeficient cells into tumors In preclinical model, the gene inhibition and pharmacological inhibition of PAK4 can effectively overcome the resistance of PD-1 antibody At present, the phase I clinical trial (nct02702492) to investigate the potential of kpt-9274 (jointly developed by NASDAQ listed company karyopharm therapeutics and China biopharmaceutical company Deqi pharmaceutical) in the treatment of lymphoma and solid tumor is in progress The clinical research of kpt-9274 combined with PD-1 antibody opdivo promoted by the new research will be carried out in the near future Finally, it is worth mentioning that Antoni Ribas, a medical professor who led the study, pointed out that because the analysis showed that the expression of PAK4 was related to T cell infiltration in a variety of cancers, the results of this study may also be extended to other tumor types that did not respond to PD-1 blocking, such as pancreatic cancer Field: immunotherapy Magazine: nature cancer Highlight: scientists from UCLA have proposed a potential new strategy to overcome the resistance of PD-1 antibody - combined with PAK4 inhibition By analyzing RNA sequencing data from patients' biopsies, the researchers found that PAK4 was abundant in tumor samples with poor immune cell infiltration, and proved that PAK4 was an effective target for reversing PD-1 blocking drug resistance.