A small molecule drug that specifically inhibits cyclin D-CDK4 and D-CDK6 kinase activity has shown early promise as a potential treatment for some types of breast cancer and T cell acute lymphoblastic leukemias (T-ALL), researchers claim.
A team at the Dana Farber Cancer Institute and Harvard Medical School generated strains of engineered mice that lacked individual D-cyclins, to see the effects on tumor development. Their results showed that cyclins D1 and D3 are essential for the maintenance of some types of tumors, but can be knocked down or inhibited globally without affecting the animal’s general health or development.
Effectively, shutting down cyclin D1 production or inhibiting cyclin D-associated kinase activity in mice carrying ERbB2-driven breast tumors stopped tumor growth in its tracks by triggering the cells to go into senescence. Similarly, knocking out cyclin D3, or inhibiting cyclin D-associated kinase activity, led to tumor cell death in mice with Notch1-driven T-ALL.
Treating mice carrying either of these types of tumors using PD 0332991 mimicked the effects of cyclin D1 or cyclin D3. In the breast cancer model the drug halted tumor progression and triggered tumor cell senescence. In mice carrying the Notch1-driven T-ALL, treatment with PD 0332991 led to significant reductions in the number of leukemic cells in the blood and tumor cells in peripheral organs, and dramatic improvements in the animals’ survival. In this case the drug therapy mimicked the effects of cyclin D3 knockdown, by inhibiting cell cycle progression and triggering tumor cell apoptosis.
The drug also caused cell cycle arrest and apoptosis of a human T- ALL cell line that harbored an activating Notch1 mutation, but not human T-ALL cell lines without Notch1-activating mutations, B cell ALL lines, or other leukemic cell lines. Encouragingly, when PD 0332991 was used to treat mice carrying established human T-ALL xenografts, tumor progression was suppressed, and survival was significantly prolonged.
The team then looked at the gene expression profiles of breast cancer and T-ALL cells that were susceptible to PD 0332991 treatment, and found three basic sets of genes that were altered as a result of treatment. The first group of genes demonstrating changed expression as a result of drug therapy was common to both the T-ALL and breast cancer cells, and included a large number of downregulated cell cycle genes. The second group of genes demonstrated changed expression in drug-treated T-ALL, but not breast cancer cells, and was enriched for apoptosis-related genes. The third group was altered in PD 0332991-treated breast cancer cells, but not T-ALL cells, and included a large number of cell-division genes.
“Collectively, these results reveal that individual D-cyclins are not required for normal mouse physiology, but they are absolutely essential for tumor maintenance,” the researchers report in their published paper in Cancer Cell. “Hence, by targeting particular D-cyclins, or by inhibiting their associated kinases, one can selectively kill tumor cells or irreversibly arrest their proliferation by triggering tumor cell senescence, without affecting normal tissues.”