Agents that inhibit tumor growth by targeting the regulatory protein CDK4 might actually promote the growth of B-cell lymphomas, a new study indicates.
Researchers found that inhibiting CDK4 promotes genetic instability and the development or progression of B-cell lymphomas driven by the Myc oncogene.
The team said this suggests that CDK4 inhibitors should be used cautiously, particularly in patients with B-cell lymphomas.
The findings also raise the possibility that these inhibitors work through off-target effects and require further investigation.
The research was published in The Journal of Clinical Investigation.
“Anti-CDK4 strategies are being widely tested as broad-spectrum anticancer therapies,” said study author Xianghong Zou, PhD, of The Ohio State University Comprehensive Cancer Center.
“Our findings indicate that anti-CDK4 strategies must be carefully tailored because they might have unexpected lymphoma-promoting effects.”
Dr Zou and his colleagues used an Eμ-Myc transgenic mouse model of B-cell lymphoma to study the role of CDK4 in lymphoma. And they found that loss of CDK4 accelerates Myc-driven lymphomagenesis, augments the genomic instability of MYC-expressing B cells, and enhances the tumorigenic potential of Myc-driven lymphoma.
The researchers also assessed the role of CDK4 in 2 human Burkitt lymphoma cell lines, Ramos and CA46, which expressed modest levels of CDK4. The team found that silencing CDK4 augmented the cell lines’ tumorigenic potential when they were injected into mice.
“It was quite striking,” Dr Zou said. “Silencing CDK4 in our mouse model and in human B-cell lymphoma cells had the opposite effect of small-molecule inhibitors that are touted as selective inhibitors of CDK4 and CDK6.”
“Given that these agents have undergone limited profiling, it might be that these agents inhibit kinases other than CDK4 and that, in lymphoma cells, they promote critical factors that support cell growth and survival.”
Additional experiments showed that the lymphoma-promoting effects of CDK4 deficiency were associated with genomic instability provoked by dysregulation of a FOXO1/RAG1/RAG2 pathway. CDK4 deficiency induced Rag1 and Rag2 transcription via FOXO1.
To confirm these findings, Dr Zou and his colleagues evaluated the role of CDK4 in human B-cell lymphoma samples.
They tested 125 samples and found little to no expression of the CDK4 protein in about 90% of them. Suppression of CDK4 levels was evident in MALT lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma.
On the other hand, FOXO1 levels were highly elevated in nearly 70% of the samples. Elevated levels of RAG1 were concordant with high levels of FOXO1 and associated with reduced levels of CDK4.
According to the researchers, this suggests a CDK4/FOXO1 pathway is disabled in a “significant proportion” of non-Hodgkin B-cell lymphomas. The results also support the idea that inhibitors targeting CDK4 may promote the development and progression of lymphoma.