The next generation of CDK inhibitors is coming

Since the discovery of cyclin-dependent kinases (CDKs), a family of proteins vital in the early stages of cell development, scientists have tried to target them to disrupt the division and proliferation of cancer cells. This is especially true in breast cancer due to its reliance on this process for growth.

The first generation of these agents, known as CDK inhibitors, targeted both CDK4 and CDK6. That is why they’re known as CDK4/6 inhibitors.

One of the first Food and Drug Administration (FDA) approvals of a CDK4/6 inhibitor was based on the international, multicenter MONALEESA-7 and MONALEESA-2 clinical trials of ribociclib, which were led by MD Anderson’s Debu Tripathy, M.D., and Gabriel Horobagyi, M.D. The trials showed that, when given in combination with hormonal therapy, the inhibitor helped significantly extend the lives of breast cancer patients without disease progression.  

Now, multiple CDK4/6 inhibitors are approved for breast cancer treatment. However, they have some shortcomings. Most breast cancer patients do not respond to them. Even among those that do, there are issues of toxicity and building resistance, which limit their effectiveness.

That’s why MD Anderson researchers remain focused on studying and developing CDK inhibitors. Soon, new research may solve those issues and help CDK inhibitors reach even more patients.

The next generation: Beyond CDK4/6

Timothy Yap, M.D., Ph.D., associate professor of Investigational Cancer Therapeutics, is leading three separate trials of CDK inhibitors that will be presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. He says we’re on the verge of seeing the next generation of CDK inhibitors.

“The question with CDK inhibitors has been, what’s next?” Yap says. “And what’s next is firstly a more selective and potent next-generation CDK4-specific inhibitor without blockade of the CDK6 target. By removing that, we’re seeing fewer toxicities, and we’re able to also dial up the dosage, which may make them more effective.”

One example is PF-07220060, a next-generation highly selective CDK4 inhibitor with significant sparing of CDK6 blockade.

“Because of its greater selectivity for CDK4 over CDK6, we see less neutropenia and, consequently, can dose higher to attain tolerated drug concentrations that exceed those reported for the approved dual CDK4/6 inhibitors,” says Yap. “Preclinical tumor models have shown that PF-07220060 effectively suppresses tumor growth in CDK4/6 inhibitor and endocrine therapy-resistant models.”

Yap says the early Phase I clinical trial data he is presenting are encouraging. These initial results suggest that these new CDK4 inhibitors are not only potentially better tolerated and more effective for new patients; they can also help overcome resistance in patients previously treated with CDK4/6 inhibitors.

Along with better targeting of CDK4, the next generation of CDK inhibitors is also taking aim at CDK2. Yap has been leading a Phase I trial of PF-07104091, which is a potent and novel CDK-2 selective inhibitor, as well as a study of BLU-222, a CDK2 inhibitor also under Phase I trial investigation. The justification for targeting CDK2 is based on research like the work being done in the lab of Khandan Keyomarsi, Ph.D., professor of Experimental Radiation Oncology. 

“Robust preclinical research has shown that there are certain tumor types that have the potential for increased levels of certain biomarkers, such as cyclin E and CDK2 activity and/or loss of the Rb tumor suppressor,” Keyomarsi says.

The future of CDK combinations

These novel results open the door to several possibilities that Yap, Keyomarsi and others are currently exploring. In particular, the next-generation CDK4-selective or CDK2-selective agents in combination with endocrine therapy, respectively, showed promising antitumor activity in heavily pre-treated patients with hormone receptor positive, HER2 negative metastatic breast cancer who had stopped responding to their prior CDK4/6 inhibitor treatment and endocrine therapy.

Yap believes that a few years from now we’ll see greater use of these next-generation CDK4-selective and CDK2-selective drugs in different combination strategies in certain breast cancer patients.

Even larger possibilities are also on the horizon. For example, cyclin E is a protein that binds with CDK2 early in the cell cycle. When overexpressed, it has been shown to be a primary driver of cancer in patients across different tumor types.

“In pre-clinical models, inhibition of CDK2 showed anti-tumor activity in multiple cyclin E-aberrant cancer types,” Keyomarsi says. “Potentially leading to clinical strategies that could lead to the expansion of CDK2 inhibitor use in and beyond breast cancer.”

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