Although the research on the chemotherapeutic drug cisplatin has been carried out for several decades, until recently, the research on its mechanism of action has gradually begun to develop. Researchers at the Winship Cancer Research Center at Emory University have recently discovered an enzyme that produces cisplatin resistance in tumors and cancer cell lines, and have discovered a new drug, letaurtinib, that inhibits the enzyme. The findings were recently published in Cancer Cell. This is undoubtedly good news for patients suffering from cancer.
Cisplatin is a chemotherapy drug that damages DNA and is used as a standard treatment for lung cancer, head and neck cancer, ovarian cancer, and testicular cancer. Its structure is very simple. After entering the body, the platinum element crosses with two or double strands in the single strand of DNA to create a bond. Although it can treat many cancers, in some cases, cancer cells develop resistance.
Dr. Sumin Kang of the Winship Center and colleagues decided to look for enzymes necessary for cancer cells to be resistant to cisplatin treatment. They chose kinases as subjects. Kinases can control cell growth in a number of ways, and many drugs have targeted them. The researchers found that when the sublethal dose of cisplatin coincides with the inhibition of MAST1, it kills cancer cells. What is the mechanism behind this combination? The researchers found that studies of cancer cell lines and human primary tumor samples showed that levels of MAST1 are associated with cisplatin resistance.
Graphic of this study (Source: "Cancer Cell")
The next step in the research will be to find compounds that inhibit MAST1. Dr. Kang's team found that the kinase inhibitor lestaurtinib is expected to inhibit this. This kinase inhibitor has been used in clinical trials in a variety of cancers such as acute myeloid leukemia (AML). Surprisingly, lestaurtinib was originally thought to inhibit another enzyme (tyrosine kinase) rather than MAST1 (threonine kinase 1). "This discovery has given us more direction to develop, including the continued development of lestaurtinib and the development of other kinase inhibitors," Dr. Kang said. "The removal of MAST1 does not have an excessive effect on cell toxicity." We believe that targeting MAST1 will be superior to targeting MEK1." She also said that the combination therapy is expected to double the dose of cisplatin in order to reduce the side effects of patients.
It is worth mentioning that the lestaurtinib used in this study has entered other clinical trials, so it can be added to new clinical trials to test cisplatin-resistant tumors.
In animal models of tumor implantation, cisplatin can be used in combination with lestaurtinib to treat a variety of cancer cells, including head and neck squamous cell carcinoma, lung cancer, ovarian cancer, and cervical cancer. Targeting MAST1 therapy is expected to bring good news to patients with advanced cancer, as well as to some patients who have received cisplatin therapy but developed resistance. We expect this therapy to bring the gospel to patients as soon as possible.
Reference materials:
[1] Overcoming resistance to a standard chemotherapy drug
[2] MAST1 Drives Cisplatin Resistance in Human Cancers by Rewiring cRaf-Independent MEK Activation
Source: WuXi PharmaTech
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