The researchers understand why a popular therapy for the treatment of colon cancer often eventually stops working: The tumors naturally carry genetic changes that allow certain their cells to evade the drugs and continue to grow. The good news is that doctors may be able to detect these changes in patients' blood, then stop the cancer with another drug before it can grow again to a dangerous size.
Many people with advanced colon cancer are treated with proteins called antibodies that target a weakness of the tumor, a protein that stimulates the growth of cancer cells called EGFR. Antibodies often shrink tumors, but cancer usually comes back within 18 months. To investigate how this developed resistance, a team led by geneticist Alberto Bardelli from the Institute for cancer research and cancer treatment in Candiolo, Italy, increased colon cancer cells in boxes containing a growth medium laced with cetuximab anti-EGFR antibody called. The group now reports in Nature as the cells have become resistant to the drug because of changes in KRAS , a gene encoding a protein that may reactivate the growth path of EGFR when EGFR is itself blocked. The resistant antibody producing cells had mutations in KRAS and sometimes contain additional copies of the gene. The researchers also found these changes in biopsies of six patients with tumors that were resistant to cetuximab or a similar drug called panitumumab.
The blood of a cancer patient typically contains traces of DNA of the tumor. The Italian team and a separate group led by Luis Diaz oncologist at Johns Hopkins University in Baltimore, Maryland, have now found independently that KRAS mutations are detectable in blood samples from patients whose tumors have become resistant to drugs, Bardelli technology called a "liquid biopsy." the warning signs in KRAS appeared up to 10 months before the tumors become large enough to detect various standard imaging techniques such as X-rays. This suggests that clinicians could monitor patients' blood for resistance mutations and when they appear, give patients a second drug that also blocks the path of growth of EGFR, but in a way that KRAS mutation can not replace. the combination of such a drug called a MEK inhibitor with cetuximab killed colon cancer cells in a laboratory dish that were resistant to cetuximab alone group Bardelli reports.
"The concept of liquid biopsy, both groups used, is really a step forward, and I am sure it will be widely used in the clinic," said Bardelli, named online work today in Nature and the study of the Hopkins group.
another question was how resistance mutations got there. they were present in a few cells before the patient was treated with the drug, or did they occur after treatment? to find out, the team and his Hopkins colleagues at Harvard University have developed a mathematical model of the genetic evolution of the tumor that match their data KRAS mutations in the blood. They concluded that resistance mutations resulting from spontaneous changes in DNA that cells divide are present in some tumor cells even before the treatment. The model shows that the resistance is a "done deal", Diaz and his colleagues write. It is also probably inevitable for other so-called targeted therapies, such as those for melanoma and lung cancer, which also generally work for less than a year, Diaz said.
"The lessons here that resistance mutations occur spontaneously" into a tumor, even before therapy is tried, said Diaz. In rare cases, a patient-targeted therapy lived for years without develop resistance. But these tumors may be very young when the patient is first treated, or abnormally slow growth, Diaz said.
"these results are illuminating and sobering" because they show that resistance drug against the target colon cancer is inevitable, says oncologist Neal Meropol of Case Western Reserve University in Cleveland, Ohio. The treatments will target more than one molecular pathway, he said.
But Dominik Wodarz evolutionary biologist at the University of California, Irvine, also found the Hopkins study "encouraging" because the model seems to describe drug resistance in cancer and diseases such as HIV who are "very different from each other biologically." Although cancer is complex, given that its dynamics are "relatively simple" craft will help researchers better treatments, he said.
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