Already-promising cancer drug may have wider applicability

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In a new study, the researchers describe how the drug palbociclib not only interferes with cancer cell division but, in tumors with high amounts of a protein complex called D3-CDK6, triggers metabolic changes that can cause the cancer cells to die. The findings, published online today by the journal Nature, suggest that palbociclib could be uniquely effective in patients whose tumors carry elevated levels of D3-CDK6.

The authors note that the research, which was conducted in laboratory cell lines and mouse models engrafted with human tumors, needs to be expanded to include additional cancer types and tissue samples, but if the results are similarly positive, it could mean the potential of palbociclib and similar agents has only begun to be tapped.

“Palbociclib is one of three agents that inhibit the enzymes CDK4 and CDK6, which are elevated in many cancer types,” says Dana-Farber’s Peter Sicinski, MD, PhD, the study’s senior author. “They’ve shown promising results in clinical trials but have a limitation. CDK4 and CDK6 drive the process of cell division: inhibiting them may hold tumor cell division in check, but doesn’t eliminate the cancer. Patients may need to take these drugs indefinitely.”

In previous research, researchers at Dana-Farber and elsewhere found that in one type of cancer – T-cell acute lymphoblastic leukemia (T-ALL) – palbociclib had a dual effect: halting the division of tumor cells and causing them to undergo the programmed cell-death process apoptosis. Sicinski and his team set about exploring the source of this difference.

In a series of experiments, Haizhen Wang, PhD, of Sicinski’s lab, found that in T-ALL, a complex made up of CDK6 and a protein “cyclin” called D3 help control cell metabolism (the chemical processes that keep cells alive). The D3-CDK6 amalgam, she discovered, controls the production of substances that protect cells from entering apoptosis. Blocking D3-CDK6 with palbociclib robs T-ALL cells of that protection, causing them to die.

“In breast cancer cells, for example, palbociclib inhibits a different complex, called D1-CDK4,” Sicinski notes. “This stops the cells from dividing but doesn’t kill them.”

Wang then analyzed a library of more than 1,000 tumor cell lines to identify those with the highest and lowest levels of D3-CDK6. When she treated the latter group with palbociclib, they underwent cell cycle arrest but not death. Those with high D3-CDK6, by contrast, died.

It’s not known what proportion of cancers have high amounts of D3-CDK6, but Wang estimates it to be 5 to 15 percent, encompassing a wide array of cancer types.

Taking the research a step further, she worked with Novartis Institutes for Biomedical Research, the developer of another inhibitor of CDK4 and CDK6, ribociclib, to study the drug’s effectiveness in mice engrafted with human tumor tissue. As in the experiments with tumor cell lines, human tumors with high D3-CDK6 levels essentially disappeared when the mice were treated with ribociclib.

“If our results are validated by additional research, it raises the prospect of testing patients’ tumors for D3-CDK6 levels to determine which are most likely to benefit from treatment with palbociclib or other CDK4 or CDK6 inhibitor,” Sicinski says.

The research was supported by the National Institutes of Health (grants R01 CA083688, R01 CA202634, P01 CA080111, R01 CA163698, F32 CA165856, P50 CA090381-14, and post-doc training grant T32CA009361); a James and Shirley Curvey MGH Research Scholarship; and a Mobilność Plus fellowship.

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