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ASCO: Mechanisms of Resistance to Targeted Therapies


At the 2012 meeting of the American Society for Clinical Oncology in Chicago this week, the Dana-Farber Cancer Institute's Levi Garraway chaired a session on research into different mechanisms of resistance to targeted anti-cancer therapeutics. In his research on melanoma, Garraway says he's seen that there are a number of mechanisms tumor can use to reactivate the pathways that sustain them. For example, in the MAP kinase pathway, RAF inhibitors, MEK inhibitors, and ERK inhibitors could all be used to block melanoma cell proliferation. Vemurafenib has even been shown to improve survival in patients with BRAFV600E-mutated melanoma. But resistance is pervasive, Garraway said. That resistance can come from C-RAF activation, NRAS mutation, BRAF splicing, MEK activation, and other mechanisms, he added. They can all lead to a reactivation of the disease pathway and disease progression, but how they do so isn't very well understood. "Our knowledge of individual mechanisms is not saturated," Garraway said.

There are several experimental approaches to study resistance, however. Researchers can study cell lines, mutagenic approaches to understand resistance at the level of the target, systematic gain-of-function or loss-of-function screens, mouse models — particularly the use of patient-derived xenografts — and tumor samples from patients who have been treated. Garraway said he's found a combination of targeted pathway resistance models and GOF/LOF screens seem to work best for his purposes. Importantly, he added, researchers need to think ahead of resistance to the next possible target that could be treated in combination with other targets.

Also on the panel was the University of Torino's Alberto Bardelli, who described his lab's method of studying resistance in colon cancer using "xenopatients" and "liquid biopsy." His team transfers tumors from individual patients into mice to study how disease could progress and become resistant to treatment. They also use blood samples to detect KRAS mutations that could be indicative of possible developing resistance to EGFR inhibitors. These liquid biopsies can indicate the beginnings of resistance and disease progression months before tissue biopsy or CT scan, Bardelli said.

And the University of California, San Francisco's Neil Shah, whose research is on AML and CML, says it's important to study the tumor microenvironment for mechanisms of resistance. Recent studies have shown that insufficient target inhibition can lead to resistance, as well as SNPs in non-target genes, he added.

Cancer Minute's sister publication Daily Scan has news from ASCO's opening session here.

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