Turning Off Essential Oncogene Restricts Lung Cancer Stem Cells Proliferation

Scientists at the Mayo Clinic campus in Florida have reason to believe that the lung cancer oncogene, PKCiota, is responsible for the proliferation of lung cancer stem cells. Hence, switching this off could act as a key for the treatment of this deadly disease.

These stem cells are rare and powerful master cells that manufacture the other cells that make up lung tumours, and are resistant to chemotherapy treatment.

The study also shows that an agent, aurothiomalate, being tested at Mayo Clinic in a phase I clinical trial substantially inhibits growth of these cancer stem cells.

"Our data indicate that PKCiota is required for the earliest steps in the development of lung cancer, which is the expansion of tumor-initiating cells or cancer stem cells," said the study's senior author, Dr. Alan Fields.

"Lung cancer stem cells appear to be the major drivers in many common lung cancers, and in order for a therapeutic treatment to be effective, it has to disrupt these cancer stem cells. We show that aurothiomalate, the agent now being tested in lung cancer patients, can, in fact, target these cells," he added.

While aurothiomalate was once used to treat rheumatoid arthritis, the researchers have now discovered that it can also target PKCiota.

Currently, the agent is being tested in patients at Mayo Clinic's sites in Minnesota and Arizona and, based on this phase I trial, a phase II human clinical trial is planned to combine aurothiomalate with agents targeted at other molecules involved in cancer growth.

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"We had previously shown that PKCiota is required to maintain tumor growth, but what this study sought to determine is whether PKCiota is involved in the initial steps of lung cancer development," said Fields.

Fields said that, in mice, an oncogene known as Kras is thought to transform normal lung stem cells into cancer stem cells, thereby initiating lung cancer.

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In the present study, the researchers established a strain of mice in which Kras can be activated at the same time that the PKCiota gene is inactivated.

They found that when the PKCiota gene is inactivated, Kras was unable to cause errant growth and expansion of lung stem cells in mice, the process that initiates tumour formation.

"What this told us is that Kras requires PKCiota to transform the lung stem cells and make them proliferate. In other words, PKCiota is downstream from Kras, and is necessary for Kras to initiate lung tumor formation," said Fields.

After discovering that aurothiomalate disables PKCiota, the researchers tested whether this agent is effective against lung cancer that develops due to Kras mutation.

"The drug showed potent inhibitory effects on the Kras-dependent proliferation of lung cancer stem cells both in cell culture and in animals," said Fields.

"That further suggests that a drug like aurothiomalate could have an effect on tumors that are dependent on either Kras or PKCiota for growth and survival, and that is potentially a lot of cancers.

Aurothiomalate appears to be one of the few drugs available that can effectively target these critical cancer stem cells. In the clinic, however, it is likely that aurothiomalate will be most effective when combined with other agents designed to target other tumor survival pathways," he added.

The study has been published in Cancer Research.

Source-ANI
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