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AACR: Understanding Tumors with Cancer Genomics

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Monday's AACR session kicked off with a plenary session on the future of cancer genomics. The Broad Institute's Levi Garraway discussed the big picture of cancer genomics, saying that although the prospect of curing solid tumors seems far away — and rather daunting — the key to understanding therapy resistance, and therefore to giving clinicians a chance to better treat their patients, is in using genomics approaches. Treatment resistance continues to be a problem, although the advent of combination therapies is starting to address this problem. Cancer genomics, Garraway said, helps in understanding tumor dependency, developing therapeutics, and understanding how best to get a response from a tumor. Garraway concentrated on one example to illustrate his point — melanoma. Years ago, research showed that RAF and MEK act in melanoma, and RAF and MEK inhibitors were developed to treat patients. However, resistance to these treatments is occurring, and the way forward is to understand the resistance mechanism and optimize therapy by creating effective combinations of drugs. New research into the genomics of melanoma has now elucidated several kinases, like COT and C-RAF, that can cause RAF inhibition resistance, Garraway said. COT had never been implicated in human cancer before, he added, and C-RAF activation has now been shown to confer resistance to RAF inhibition. Using various genomics approaches, researchers have modeled sensitivity to RAF inhibitors in several genes, and have found COT expression in oncogenic BRAF cell lines, which suggests that COT plays a role in resistance. To make this research relevant to the clinic, Garraway and his team looked at melanoma patient tissue samples and found progression of COT expression during treatment and post-relapse. COT isn't entirely to blame for resistance, but does mediate it, Garraway said. And it would not have been found without a systematic genomic approach. Systematic functional genomics "lays out the landscape of resistance," he added.

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