Study Finds Key to Drug Resistance.
Study Finds Key to Drug Resistance
Sophisticated “targeted” drug therapies are improving cancer care by selectively shutting down abnormal growth switches in tumor cells while avoiding toxicity to normal tissues. In some cases, though, tumors that are initially sensitive to these drugs first regress but then activate different, “backup” genetic signals that enable them to circumvent the therapy.
A new discovery by Jean Zhao, HMS associate professor of biological chemistry and molecular pharmacology at Dana-Farber Cancer Institute, and colleagues may help physicians predict which tumors are likely to become resistant to a given drug, and identify the secondary pathways they are activating to escape the original therapy.
The discovery could lead to tests of a patient’s tumor that would tell doctors they need to utilize an additional drug during therapy to block tumor growth via the secondary gene abnormality.
“We are trying to be a step ahead so we can inform the scientists conducting the clinical trials of what to expect,” explained Zhao. “If we can identify potential drug resistance mechanisms, we can more rapidly design combination drug therapies to overcome the resistance.”
In the report, published by Nature Medicine, researchers described how they created a genetically engineered mouse model of human breast cancer in which the most frequently occurring breast cancer “oncogene,” PIK3CA, could be turned on and off.
Surprisingly, the researchers found that while all of the PIK3CA oncogene-induced breast tumors initially shrank following inhibition of the oncogene, a large fraction of tumors shrank partially and then later resumed growth. Moreover, about half of these recurrent tumors did not respond to PI3K inhibitors currently in clinical trails for cancer therapy, meaning the cancer cells were no longer dependent on the PI3K pathway to survive.
The scientists performed genomic and genetic analyses on a large collection of recurrent tumors and found that about 30 percent of recurrent tumors have either an increased copy number or higher expression levels of another common oncogene known as c-MYC, which is independent of the PI3K pathway. These tumors were not sensitive to PI3K inhibitor treatment. When the researchers used a molecular tool to block c-MYC activity, it suppressed the growth of these recurrent tumors.
More importantly, the researchers analyzed multiple samples of human breast tumors, revealing that more than 30 percent of those tumors that carry the PIK3CA mutation also contained high levels of c-MYC.
At this time there aren’t good drugs to block c-MYC in cancer, Zhao noted. Nevertheless, she said the experimental results suggest it would be useful to test patients’ breast cancers for c-MYC when they’re being treated with PI3K inhibitors to alert doctors to the likelihood of tumor recurrence.
And eventually, Zhao added, “I’m optimistic that we can overcome tumor resistance caused by increased c-MYC abundance.”
The research was funded by a grant to the Stand Up to Cancer PI3K Dream Team, led by Lewis Cantley, HMS professor of systems biology at Beth Israel Deaconess Medical Center. Cantley commented, “This is a signature paper from our Stand Up to Cancer PI3K Dream Team and serves as an example of how genetically engineered mouse models can provide a powerful framework for identifying mechanisms that circumvent oncoprotein inhibition. Understanding this mechanism will greatly improve development of targeted therapy.”
As a measure of the journal article’s importance, it has been picked for inclusion in a library of the top 2 percent of published articles in biology and medicine by The Faculty of 1,000, an organization of scientists that evaluates biomedical publications.
By Richard Saltus
Originally published by Dana-Farber Cancer Institute.
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