Cancer cells rebound despite anticancer drugs ... No resistance when two drugs are combined [Health LAB]

[Financial News] Anticancer drugs kill cancer cells by damaging their DNA. But if cancer cells repair the damaged DNA themselves, they survive, and even drugs that had been working well gradually become less effective. Researchers in South Korea have found a way to put the brakes on this “repair ability” of cancer cells and boost the effectiveness of next-generation cancer drugs.
According to POSTECH (Pohang University of Science and Technology) on the 16th, Professor Kim Tae-kyung of the Department of Life Sciences and Graduate School of Convergence Science, and Jeong Hye-rim, a student in the integrated program, worked with researchers at Qurient to show that using the drug candidate mocaciclib (Q901) together with antibody-drug conjugates (ADCs) significantly boosts anticancer efficacy, and to identify how it works. The findings were published in the international journal Science Advances.
ADCs are a type of “guided-missile” cancer drug: they use antibodies that seek out cancer cells to deliver potent anticancer agents. Enhertu (T-DXd) and Trodelvy (SG) are prominent examples; both carry drugs that damage cancer cells’ DNA. The problem is that their effectiveness declines as cancer cells build up their DNA repair capacity, and resistance to one drug can spread to other, similar ADCs.
The researchers focused on CDK7, an enzyme that “starts” genes. For cells to make proteins, they first have to read genes, and CDK7 provides the signal to start. Mocaciclib, which Qurient is developing clinically, is at least 200 times as selective for CDK7 as for similar enzymes.
Mocaciclib kept CDK7 inhibited at the starting line of genes, preventing RNA polymerase, which reads genes, from starting. As a result, the activity of proteins that drive cancer growth (MYC and E2F) declined, as did the expression of genes cancer cells use to repair DNA damage.
Also, DNA damage left by ADCs only begins to be cleared when an enzyme moving along as it reads genes collides with the damage. Since the enzyme could not even start, no collision occurred, and the damage continued to accumulate in the cancer cells. In effect, the treatment both reduced the genes involved in repair and eliminated the chance for the repair process to begin.
The effects of using the two drugs together were confirmed in models of small-cell lung cancer, colorectal cancer and lung cancer. In an animal model of colorectal cancer under conditions where Enhertu is unlikely to work well, the tumors stopped growing when the two drugs were administered together. The tumor growth inhibition rate was 102%. When only one drug was administered, the tumors began growing again after about 11 days, but the effect lasted throughout the experimental period when the drugs were combined. Tumor suppression also increased when the treatment was combined with Trodelvy.
Professor Kim Tae-kyung of POSTECH, who led the study, said, “We have identified how selective CDK7 inhibition blocks DNA damage repair through transcriptional regulation and enhances the efficacy of ADCs,” adding, “This could offer a new treatment strategy for patients with low levels of target proteins or who need to reduce their dosage because of side effects, as well as for patients who use multiple ADCs in sequence.”

[email protected] Yeon Ji-an Reporter