Pancreatic Cancer. Pancreas Model
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UNC Lineberger Comprehensive Cancer Center researchers and colleagues, via two separate articles “Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers,” and “Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer,” published today in Science, say they have developed the most comprehensive molecular portrait of the oncogene KRAS and how its activities affect outcomes for pancreatic cancer. The research could help clinicians to select more targeted treatment options for pancreatic cancer patients.

“Because less than 40% of pancreatic cancers respond to treatment with KRAS inhibitors, if we can establish molecular markers to predict which patients will respond, we can better provide them with specific treatments, which should improve their outcomes,” said Channing J. Der, PhD, a professor at UNC School of Medicine’s department of pharmacology and a corresponding author of both articles. “From diagnosis to death, the average pancreatic cancer patient treated with chemotherapy lives 6 to 12 months, so there’s a very limited time to offer a treatment which will work.”

While KRAS is one of the most commonly mutated genes across all cancer types, and is present in more than 90% pancreatic cancers, its mechanisms for promoting cancer growth are still largely unknown. This knowledge gap was the basis of the new findings from the Lineberger team.

In what they describe as the most detailed analysis of KRAS to date, the investigators showed that the molecular pathway most responsible for the cancer-promoting functions of the oncogene is highly dependent on the ERK protein. ERK regulates which genes are expressed and which proteins are active. The ERK protein has been broadly studied since it is known to be a significant player in the function of KRAS, but its role has remained unclear.

The two papers published by the team leverage improvements in methods to study cellular signaling and found that ERK regulates the expression of a complex array of thousands of genes and can change the function of thousands of proteins. Importantly, the research also confirmed their findings in cancer models could accurately predict treatment responses in patients treated with ERK and KRAS therapies for pancreatic, colorectal and lung cancers.

Two KRAS inhibitors have been approved for treatment to date and, since it is such a prevalent and promising target, there are a number of KRAS targeting drugs moving through clinical trials.

Work by Der and his team in two papers earlier this year published in Nature, provided details of a promising new drug that has show effectiveness against a variety of KRAS mutations. Specifically, the investigators of the earlier studies showed that the MYC oncogene can cause resistance to KRAS therapies. The papers published yesterday in Science established that MYC is a significant component of how both KRAS and ERK support cancer growth and that it is also a driver of therapy resistance to KRAS and ERK targeting therapies.

“Our next steps are elucidating more aspects of basic and foundational research regarding KRAS,” Der said. “We will continue to mine the growing body of scientific knowledge we have developed, with the ultimate goal of helping advance the clinical development of newer and better KRAS inhibitors.”

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