Treating resistant prostate cancer by depriving a key hormone of its 'co-pilot'

Blocking CDK7 can cause the death of prostate cancer cells that have spread and are resistant to standard hormone suppression therapies, scientists at the University of Pennsylvania have found. (Penn Medicine)

When prostate cancer spreads to other parts of the body and keeps growing despite hormone therapy, FDA-approved drugs like Johnson & Johnson’s Zytiga and Pfizer and Astellas’ Xtandi offer limited survival benefits. Scientists at the University of Pennsylvania's Abramson Cancer Center have now found a potential new way to battle this challenging form of the disease, which is known as metastatic castration-resistant prostate cancer (mCRPC).

The researchers discovered that blocking an enzyme called CDK7 can cause the death of mCRPC cells in lab dishes and in animal models. They published the findings in the journal Cancer Discovery.

Because prostate cancer cells usually require androgen hormones such as testosterone to grow, androgen deprivation therapy is the standard approach to treating the disease. But the cancer can become resistant to those therapies, so new approaches are needed.

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CDK7 acts as an on/off switch for a protein called Med-1, which works with the androgen receptor (AR) to drive prostate cancer growth, the Penn team has shown.

“We know that AR does not work alone; that it needs Med-1 as its partner,” the study's senior author Irfan Asangani, said in a statement. “Our study found a way to turn off Med-1, leaving AR without its co-pilot which means the cancer cannot grow and the cells eventually die.”

Inhibiting CDK7 led to CRPC cell death with limited impact on healthy cells, the team reported. “Our theory is that these cancer cells are addicted to Med-1 and AR but other cells are not, so we’re essentially cutting them off from their addiction,” Asangani said.

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Cyclin-dependent kinases (CDKs), which play a key role in cell division and transcription, have been implicated in several cancer types. Scientists at the Institute of Cancer Research in the U.K. and the University of Michigan previously found that some mutations in CDK12 could predict better responses to PD-1 checkpoint inhibitors in prostate cancer. CDK4/6 inhibitors such as Eli Lilly’s Verzenio, Pfizer’s Ibrance and Novartis’ Kisqali have proven their use in metastatic breast cancer.

Inhibitors of CDK7 are already being tested in humans for other cancer types. A team of scientists from Imperial College London created a CDK7 inhibitor that showed promise in breast cancer and also in acute myeloid leukemia.

The drug, now called CT7001, has been licensed to Carrick Therapeutics, which has started a phase 1 in breast cancer. It will also be evaluated in one cohort of up to 25 mCRPC patients, according to ClinicalTrials.gov. Syros Pharmaceuticals is also developing a CDK7 inhibitor, SY-1365, which is now in phase 1 testing in patients with advanced solid tumors.

Asangani and colleagues believe their study could inspire further testing of CDK7 inhibitors in prostate cancer.

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