CDK6 Identified as Target for ATLL

Researchers have identified CDK6 as a novel therapeutic target for adult T-cell leukemia/lymphoma (ATLL).

Currently available chemotherapies are not particularly effective in treating ATLL, which has a long-term survival rate of only 20%. Much research has been done to explore the molecular pathways and gene mutations involved in this cancer, but these vary between patients, making it difficult to develop effective treatments.

Hokkaido University hematologist Masao Nakagawa and colleagues in Japan, the US and France used CRISPR-Cas9 gene editing technology to inactivate thousands of genes in several ATLL cell lines. They identified 1,278 genes essential for the survival and proliferation of ATLL cells. They then conducted a more detailed investigation of CDK6, CCND2, BATF3, JUNB, STAT3, and IL10RB.

Among these, CDK6 proved particularly promising as a drug target. The gene CDK6 encodes an enzyme that activates cell proliferation. Nakagawa and colleagues found that inactivating the enzyme with palbociclib stopped cell division and caused cell death in some, but not all, of the tested ATLL cell lines.

The cell lines that were resistant to the drug had a mutation in TP53, which under normal circumstances is involved in inhibiting tumor growth and development. These cells died when treated with the CDK6 inhibitor palbociclib together with an activator of mutant TP53 called APR-246, a drug that is currently used to treat a type of blood cancer called myelodysplastic syndrome.

Further, Nakagawa and colleagues found that ATLL cells were dependent on mTORC1 signaling. They found that combining palbociclib with the drug everolimus, which inhibits mTORC1, also killed ATLL cells, including those with TP53 mutations. The drug combination also significantly reduced tumor growth and had minimal side effects when tested in mice with grafted ATLL tumors.

“Our study reveals CDK6 as an attractive target for treating ATLL,” Nakagawa said in a statement. “However, we also discovered that loss of TP53 function in some ATLL cell lines leads to resistance to the CDK6 inhibitor, palbociclib. Given this finding, researchers should consider the status of TP53 in future clinical trials of palbociclib in ATLL.”

Ishio T, Kumar S, Shimono J, et al. Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma. Blood. 2022;139(10):1541-1556.