Newly approved second generation of CDK4/6 inhibitors give hope to breast cancer patients

by Ilona Baraniak

Breast cancer is the most common type of cancer in women worldwide, with nearly 1.3 million new cases each year. One fourth of all diagnosed cancers in women are breast cancers, and a new case is diagnosed once every 10 minutes. It is the fifth most common cancer-related cause of death for women, and current predictions estimate a continuing rise of cases. Experts believe that 1 in 8 women and 1 in 870 men will be diagnosed with breast cancer during their lifetime.

 

Scientific breakthroughs give us hope

The scientific advancements in the past few decades broadened our understanding of molecular and cellular biology. One of the most important scientific breakthroughs was the discovery of mechanisms regulating cell division and the array of key molecules governing this process. This accomplishment was recognized with the 2001 Nobel Prize in Physiology or Medicine. This scientific milestone allowed researchers to start gaining an understanding of the processes involved in cancer development and offered potential explanations for some of the underlying mechanisms.

This in turn facilitated the design and clinical development of targeted agents against tumour cells. Despite currently having a wide range of therapeutic interventions available for clinical practice, these are far away from being optimal due to high toxicity or the possibility of developing resistance to available drugs. As these can lead to the development of fatal diseases, there is an urgent need for a better, more specific, and less toxic therapeutic approach to treat cancer. New scientific advancements give us important clues as to how such new therapeutics should be designed.

Cell division cycle disruption: a key event starting cancer development

The cell cycle is viewed as an orderly progression of distinct phases (G1, S, G2, M). Various molecules are essential in regulating this complex process, of which most belong to the families of proteins called cyclins and cyclin dependent kinases (CDK) and the RB gene product (pRb). An orderly progression between the phases is tightly controlled at 'checkpoints' through the interplay of many different cyclins and their associated CDKs.

As long as the balance between them is maintained, the cell cycle can progress uninterrupted. However, any alterations to this very complex cell division process may disrupt proper cell cycle progression and, consequently, lead to the development of cancer.

In the case of estrogen receptor-positive breast cancer, alterations in several cell cycle regulatory proteins are known to be the cause of malformations. New evidence strongly indicates that the dysregulation of the balance between D1: CDK4/6 cyclins plays an important role in the formation of this specific type of cancer.

 

Can selected pharmacological inhibition of cyclins fight off breast cancer?

Figure 1: The cell cycle and the D: CDK4/6 pathway // Breast Cancer Res. 2016 Feb 9;18(1):17. doi: 10.1186/s13058-015-0661-5.

Cell cycle regulation has long ago been identified as an attractive target for drug therapy. Due to specific involvement in cell cycle progression the CDKs were pursued as desirable drug targets (Figure 1).

So far, many drug discovery programs have studied potent small molecule CDK inhibitors, with several compounds successfully entering preclinical and early clinical trials. Until recently, however, many CDK inhibitors have shown to have very little clinical activity against the tumours. Even more disappointing, these therapies were accompanied by a range of undesirable and dangerous adverse effects.

This is believed to be a result of poor specificity of those inhibitors. Instead of targeting very specific cyclins they tend to interact with a wide range of different molecules, which in turn interfere with various cellular signalling pathways. Therefore, those drugs are associated with high toxicity and have unpredictable and serious side effects.

Despite those initial setbacks, novel scientific discoveries are offering a potential solution to this problem, focusing on CDK4/6 and D1 as primary targets. Recent experiments with rodents showed that although these molecules are required for induction of breast malignancies, their presence in the cells is not essential for mammary gland development. Such results clearly suggest that selective CDK4/6 inhibition could potentially inhibit breast cancer cells while sparing healthy tissues.


Second generation of CDK4/6 inhibitor brings hope

In general, CDK inhibitors can be broken down into two classes: first generation inhibitors, which tend to be less accurate in their ability to block certain CDKs (pan-CDK inhibitors), and second-generation agents, which target specifically CDK4/6.

This latter group has recently shown potent activity against their specific targets and a much better safety profile.

The first drug from this second generation of CDK4/6 inhibitors Palbociclib received approval in 2015 for the first-line treatment of advanced post-menopausal estrogen receptor positive breast cancer in US. The drug was approved for use in the European Union in November 2016 as a treatment for hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer either in combination with an aromatase inhibitor or, for women who have received prior endocrine therapy, in combination with fulvestrant. In December 2017, palbociclib, was accepted for use by the NHS after going through the Scottish Medicines Consortium's process for medicines used to treat very rare and end-of-life breast cancer. On April 4, 2019, the Food and Drug Administration expanded the approval of palbociclib to include men with breast cancer. The expanded approval covers the use of palbociclib, combined with an aromatase inhibitor, in men with advanced breast cancer whose tumors are hormone receptor-positive and HER2 negative—the same indication for which it’s approved in women.

On August 22, 2017 the European Medicinal Agency (EMA, extended approval on December 21, 2018) and on July 18, 2018, the Food and Drug Administration (FDA) both approved second drug in this class: ribociclib (Kisqali) in combination with an aromatase inhibitor for advanced breast cancer treatment. The drug is now approved also for premenopausal and perimenopausal women based on results from MONALEESA-7 randomized clinical trials and for postmenopausal women based on MONALEESA-3 trials.

The third drug from this class; Abemaciclib was approved for use on 28 September 2017 it in the United States by the FDA and on the 1st of October 2018 by the EMA for the treatment of advanced, metastatic breast cancers. These recent approvals are especially good news for women with advanced hormone receptor–positive (HR+), human growth factor receptor 2–negative (HER2-) cancer, as this drug, along with combination hormone therapy, can provide them with a higher quality of life.

Moreover, currently several other of second-generation CDK4/6 inhibitor candidates are also moving through clinical development with spectacular success.

Although further research is still required, it seems like we are finally getting much closer to having highly selective and minimally toxic breast cancer drugs, giving hope to millions of women to win their battle against breast cancer.

 

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