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Blocking the MK2 Pathway Sensitizes Lung Cancer Cells to DNA-Damaging Chemotherapy

By BiotechDaily International staff writers
Posted on 27 Nov 2013
Cancers with mutations in the p53 gene can be rendered more sensitive to chemotherapy with DNA-damaging agents such as cisplatin by co-treatment with a drug that blocks the function of the MK2 (p38 mitogen-activated protein kinase (MAPK)/MAPKAP kinase-2) gene.

The p53 tumor suppressor gene is the cell's critical defender against genome damage from chemicals, viruses, or ionizing radiation. The p53 protein is normally found at low levels, but when DNA damage is sensed, p53 levels rise and initiate protective measures. P53 binds to many regulatory sites in the genome and triggers production of proteins that halt cell division until the damage is repaired. Alternatively, if the damage is too severe, p53 initiates the process of apoptosis, which directs the cell to commit suicide, permanently removing the damage. Cancer cells typically contain two types of mutations: mutations that cause uncontrolled growth and multiplication of cells, and other mutations that block the normal defenses that protect against unnatural growth. P53 is in this second category and mutations in the p53 gene contribute to about half of the cases of human cancer. In these mutants, normal p53 function is blocked, and the protein is unable to stop multiplication of the damaged cell. If the cell has other mutations that cause uncontrolled growth, it will develop into a tumor.

Investigators at the Massachusetts Institute of Technology (Cambridge, USA) had found previously that in cancer cells with mutated p53, the MK2 gene helped counteract the effects of chemotherapy. When tumor cell DNA was damaged by drugs such as cisplatin, MK2 blocked cell division, giving cells time to repair the damage before dividing.

To understand this phenomenon better, the investigators genetically engineered a line of mice that spontaneously generated non-small-cell lung tumors to produce cancers with or without active MK2. The ability to generate otherwise genetically identical tumors in individual mice that differed in only a single genetic locus and monitor their response to treatment allowed direct in vivo analysis of synthetic lethal interactions in a solid tumor model.

The investigators reported in the November 14, 2013, online edition of the journal Cell Reports that before treatment, tumors lacking both MK2 and p53 grew faster than tumors that lacked p53 but had MK2. However, tumors that lacked both p53 and MK2 shrank dramatically when treated with the drug cisplatin, while tumors with functional MK2 continued to grow following treatment. Normal host tissues were protected from the enhanced toxicity of MK2 inhibition due to the presence of functional p53.

"Our data suggested if you block the MK2 pathway, tumor cells would not recognize that they had DNA damage and they would keep trying to divide despite having DNA damage, and they would end up committing suicide," said senior author Dr. Michael B. Yaffe, professor of science at the Massachusetts Institute of Technology. "What our study really says is that these drugs could have an entirely new second life, in combination with chemotherapy. What we found is a combination that you would never have arrived at otherwise. It is a nonobvious combination. We are very much hoping it will go into clinical trials for cancer."

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Massachusetts Institute of Technology


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