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Study shows that combining two targeted therapies could overcome drug resistance in pancreatic cance

Mouse pancreatic tumors were significantly smaller after being treated with a combination of KRAS inhibitor MRTX1133 and ERBB inhibitor Afatinib (bottom row), compared to no treatment (top row) or being treated with Afatinib (second row) or MRTX1133 (third and fourth rows) alone. Image Credit – UC San Diego

CANCER DIGEST – July 14, 2023 – The first study combining a drug FDA-approved to treat certain types of non-small cell lung cancer with a recently FDA-approved investigational new drug shows that the combination can overcome drug resistance in human pancreatic cancer.

The study was published in the June 28, 2023 journal Cancer Research. The study demonstrated that blocking the action of two genes in human pancreatic cancers in cell models and in mice successfully overcame stubborn drug resistance that makes pancreatic cancer so difficult to treat.

In previous experiments, the University of San Diego researchers led by co-senior investigator Herve Tiriac, PhD showed that blocking a group of genes called KRAS in pancreatic cancer caused the cancer to activate another group of genes called ERBB, which compensated for the blocked KRAS gene. In other words the research team demonstrated that when the product of KRAS was blocked, the product of ERBB increased, allowing the cancer to resist treatment and continue growing.

To try to overcome this potential cause of drug resistance the researchers tested a combination of a new investigational drug, called MRTX133, that targets the KRAS genes with an drug, called afatinib (Gilotrif®) already approved for treatment of non-small lung cancer that targets ERBB.

They investigators first tested the combination in human pancreatic cancer cells in the laboratory, and then in mice that hosted human pancreatic tumors. They found in both experiments that the combination treatment was dramatically more effective and less prone to resistance. In the mice the combination led to tumors shrinking and longer survival.

As a result, the researchers are cautiously recommending testing the combination in human pancreatic cancer patients.

“KRAS inhibitors have the potential to completely change the landscape of treating pancreatic cancer,” said Tiriac, in a press release. “However, we need to do a lot of upfront testing to optimize KRAS therapy, or clinical trials might get a lot of negative data.”

Sources: UC San Diego press release and the journal Cancer Research

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