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Cancers that initially respond to targeted chemotherapy become resistant to treatment, common feature of cancer across many tumor types is that patients fall back into the state of illness after apparent recovery. Cancer systems biology team at the University of California, Merced, is tackling diagnosis and treatment of therapy-resistant cancers by elucidating the network of changes within cells to identify new drug targets and circumvent cancer resistance.
Cancer is a disease of human genes, resistance to therapy might go beyond cancer mutations that alter the function of genes. It may not be new mutations that are causing resistance to drugs. The DNA can stay the same, but cancer cells adapt to therapy and outsmart the drugs by switching their gene activity. The adaptations do not affect the DNA- a hidden layer of regulation controlling the activity of genes, the epigenetic signals is responsible for whether cancer cells survive or not irrespective of the drug a patient is taking. Targeting the epigenetic signals can overcome deadly cancer resistance.
Researchers compared genetic and metabolic pathways in treatment-responsive and treatment-resistant melanomas. Melanoma is a cancer that originates in melanocytes, the cells that produce the skin-color pigment melanin. Cancer can be triggered by different things, melanoma is induced by the sun, by dangerous ultraviolet UV light damage. UV damage leaves a unique mutational footprint behind and as a result unstoppable cell proliferation is induced.
UV damage gives rise to point mutations-changes in a single letter of the 3 billion letter human genome. These mutations can interfere with signals that tell cells when to grow and divide and when to stop. Mutations in a protein called BRAF, a major signaling regulator, cause growth signals to be stuck in the “on” position and drive cancer development. Scientists have come up with drugs that target and turn off aberrant BRAF signaling, but cancer cells are smart, they can adapt to these BRAF-inhibitors.
Many patients respond to cancer treatment positively at first. However, many develop resistance and metastases. Chemotherapy might kill most of the cancer, tiny drug-resistant cancer cells manage to survive and propagate. Cancer cells adapt to therapy and outsmart the drugs. Melanoma is able to circumvent BRAF inhibitors by changing gene activity, some of the genes with reduced activity were supposed to be in close communication with BRAF and safeguarding its targets, the mutated protein that gave rise to the cancer and the main target of chemotherapy.
If essential off switches are lost, cancers can trigger the tumor cells to divide despite presence of inhibitors. The resistant cells managed to evolve in a way to bypass the signaling blockade or come up with a new way to maintain proliferation. Genes with increased activity are in metabolic pathways that allowed cancer cells to bypass BRAF altogether and continue to grow and divide. Cancer cells had essentially figured out how to survive by rewiring their metabolism in response to chemotherapy.
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