Combination treatment blocks cell growth and triggers cell death in colon cancer

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Drugs that block cancer’s growth and survival could be used in a powerful one-two combination with death-triggering cancer drugs to treat colon cancer, a new study shows.

Scientists at the Institute of Cancer Research, London, synthesised a prototype drug (CCT068127) that simultaneously targets two proteins called CDK2 and CDK9, in a collaboration with the company Cyclacel Ltd.

These proteins contribute to a loss of control of cell division and transcription – the ‘readout’ of the DNA code – respectively. Both are common features of cancer.

The researchers also showed that colon cancer cells were killed by a combination of CCT068127 and BCL2-inhibiting drugs, which trigger a form of programmed cell death called apoptosis in cancer cells.

Already optimised and in clinical trials

In the study, published in Molecular Oncology, the researchers describe the activity of CCT068127 which was developed from seliciclib, an early-generation CDK-inhibiting drug.

The new inhibitor has already been further optimised into a new experimental drug called CYC065, which was discovered at the ICR in collaboration with Cyclacel, and is currently in a phase I clinical trial in patients with solid tumours.

In the published study, which was mainly funded by Cancer Research UK and Cyclacel, the researchers treated colon cancer cells with CCT068127 or seliciclib. They found CCT068127 was the most effective.

Using a technique called x-ray crystallography in collaboration with researchers at the University of Newcastle on Tyne, the team also visualised CCT068127 in place on a specific part, or domain, of CDK2 – revealing its mechanism of enhanced potency compared to seliciclib.

The prototype drug stopped cancer proliferation by suppressing CDKs used by cells to divide and to produce other proteins, the study found.

Consequently, it also lowered levels of a protein called MCL1, a member of the BCL2 family, in tests in colon cancer cells. BCL2 family proteins can help protect cancer cells from cell death.

Effective one-two combination treatment

The researchers went on to test the prototype drug in combination with an experimental drug that blocks additional members of the BCL2 family.

They found the treatments worked more effectively together than either alone, suppressing cell proliferation while also sensitising colon cancer cells to cell death signals.

The CDK family of proteins have gained intense interest as targets for cancer drugs. ICR researchers have led major studies of CDK-inhibiting drugs, including a recent clinical trial that helped establish a CDK4/6 inhibitor in breast cancer treatment, and an important recent study of CDK8/19 inhibitors.

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New ways to treat the disease

Study lead author Dr Steven Whittaker, Team Leader in Molecular Drug Resistance at the ICR, said:

“Our study describes the activity of a potent CDK2/9 inhibitor, which blocks cancer’s growth by hitting two targets at once. 

“This is also the first study to show that we could use CDK-inhibiting drugs with other drugs that trigger cell death as an effective combination in colon cancer models.

“We found that our combination tips cancer cells away from signals that promote survival towards death, so it could lead to new ways to treat the disease.”