Palbociclib (Ibrance?; Pfizer) an oral agent that target cyclin-dependent kinases (CDK4 and CDK6), which appear to promote tumor cell proliferation in hormone-receptor positive breast cancer, is gaining notice for its ability to derail cancer cell growth, may also have a second application that renders it lethal to cancers carrying high levels of a certain protein, researchers at Dana-Farber Cancer Institute found.

In 2015 the drug received accelerated approval from the United States Food and Drug Administration (FDA) to be used together with the hormone therapy letrozole (Femara?; Novartis) as a first-line (initial) treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer.

The majority of breast cancers are referred to as HR+, meaning their cancer is stimulated to grow from exposure to the female hormones estrogen and/or progesterone. These patients are treated with endocrine therapy (sometimes referred to as hormone, or anti-estrogen therapy), which reduces the cancer cells? exposure to estrogen through varying mechanisms. Endocrine therapy has proven extremely effective in reducing HR-positive cancer growth and spread for extended periods of time.

D-type cyclins (D1, D2 and D3) and their associated cyclin-dependent kinases (CDK4 and CDK6) are components of the core cell cycle machinery that drives cell proliferation.[1]

The overexpression of cyclin D1, for example, has been confirmed in a large proportion of human cancers. It is found in the majority of breast cancer cases. Upregulation of cyclin D1 may occur as a result of gene locus alterations, aberrant transcriptional signalling or disruption of cyclin D1 proteolysis. In turn, this leads to prolonged cyclin D1-CDK4 and CDK6 activation, giving cancer cells the power to enter the cell cycle continuously and to avoid senescence and apoptosis.

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The cyclin D2-CDK4 and CDK6 complex drives efficient hyperproliferation in adenomatous polyposis coli (APC) tumor suppressor protein deficient cells. The complex plays an important role in colorectal adenoma formation and inhibition of this complex may be an effective chemopreventative strategy in colorectal cancer (CRC).

Photo 1.0: Peter Sicinski, MD, PhD, Professor of Genetics, Harvard Medical School.

Triggering metabolic changes
In a new study, the researchers describe how 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. [1]

The study’s 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.

Promising results
?Palbociclib is one of three agents that inhibit the enzymes CDK4 and CDK6, which are elevated in many cancer types,? explained 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 divison in check, but doesn?t eliminate the cancer. Patients may need to take these drugs indefinitely,? Sicinski added.

T-cell acute lymphoblastic leukemia
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. The drug halted the division of tumor cells and caused 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 noted.

?This stops the cells from dividing but doesn?t kill them,? he added.

Wide array of cancer types
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%, encompassing a wide array of cancer types.

Taking the research a step further, Wang worked with Novartis Institutes for Biomedical Research, the developer of another inhibitor of CDK4 and CDK6, riboiclib (Kisqali?; Novartis), 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.

Breast cancer experts attending the 2016 annual meeting of the European Society of Clinical Oncology (ESMO) expect that CDK4 and CDK6 inhibition cyclin-dependent kinase inhibitors will become a game changer in the treatment of advanced – metastasized – breast cancer.? However, it remains unclear if all patients benefit from this approach or whether some biomarker could be identified to use them more selectively.

?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 observed.

Last editorial review: June 14, 2017

Featured Image: Microscope Courtesy: ? 2017 Fotolia. Used with permission. Photo 1.0: Peter Sicinski, MD, PhD, Professor of Genetics, Harvard Medical School. Courtesy: ? 2017 Dana-Farber Cancer Institute. Used with permission.

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