JAK Mutations a Possible Indicator of Drug Resistance
JAK Mutations are genetic abnormalities that affect the production of red blood cells. They are often found in individuals with polycythemia vera, as well as a number of other myeloproliferative neoplasms.
The anti-PD-1 agent, Keytruda (pembrolizumab) was approved in 2014 by the U.S. Food and Drug Administration for the treatment of advanced melanoma. Since then, it has received approval for two other cancer indications, advanced non-small cell lung cancer and head and neck cancer, and has helped a lot of patients live longer.
Together with other PD-1 blockers, Keytruda have presented durable responses in advanced cancers, but studies have shown that almost 25% of melanoma patients who initially responded to Keytruda had disease progression within 21 months.
Keytruda is unlikely to benefit patients whose cancers have alterations in the JAK1 or JAK2 genes, showing that such mutations lead to the loss of PD-L1, which is required for Keytruda to be effective, according to a new UCLA study.
The study, “Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations,” explains in detail why particular colon cancer and melanoma patients do not respond to this promising immunotherapy. It was published in Cancer Discovery.
To further understand the mechanisms causing this conflict, Antoni Ribas, MD, director of the UCLA Jonsson Comprehensive Cancer Center Tumor Immunology Program, together with his colleagues, conducted a study analyzing tumor samples before and after immunotherapy, and after tumor relapse. They discovered that one tumor lost the B2M gene, leading to a malfunction of the JAK1 and JAK2 proteins, which affected how the immune cells recognized the cancer.
Dr. Ribas and his team explained that the alterations in the JAK1 and JAK2 proteins encouraged the loss of reactive PD-L1 expression. Since Keytruda prevents the interaction between PD-1 and PD-L1, it doesn’t work in cancer cells with missing PD-L1 anymore.
They studied samples from 23 melanoma patients and 16 colon cancer patients. Two patients (one with melanoma and one with colon cancer) had JAK1 or JAK2 inactivating mutations and did not respond to anti-PD-1 therapy.
More studies in 48 melanoma cell lines has shown a lack of PD-L1 expression due to JAK mutations preventing the cells from responding to interferon gamma signaling.
These findings imply that JAK mutations could be used to foresee which patients are likely to respond to anti-PD-1 therapies like Keytruda or Opdivo (nivolumab).