Pathway Affecting Pancreatic Cancer Progression and Treatment Response Detailed

Researchers from the UNC Lineberger Comprehensive Cancer Center and their colleagues have compiled the most detailed molecular analysis of the KRAS gene, a crucial oncogene, and its effects on pancreatic cancer. This gene is one of the most frequently mutated in various human cancers, found in over 90% of pancreatic tumors. Despite its prevalence, the mechanisms by which KRAS promotes cancer growth remain poorly understood. The researchers aimed to uncover the genes and proteins that interact with KRAS to make its expression so deadly.

Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Despite its deadly nature, less than 40% of pancreatic cancer patients respond to KRAS inhibitor treatments. "If we can identify molecular markers that predict which patients will respond to KRAS inhibitors, we can tailor treatments to improve outcomes," said Channing J. Der, PhD, a distinguished professor at UNC School of Medicine and a corresponding author of the studies.

Published in two articles in the journal Science, the research provides significant insights into the molecular pathways influenced by KRAS. It was found that a protein called ERK plays a critical role in the cancer-causing functions of KRAS. ERK regulates both gene expression and protein activity, making it a significant player in the KRAS pathway. Although ERK has been extensively studied, its precise role and relative importance in KRAS function were not fully understood until now.

The studies revealed that the activation of ERK is the main driver of resistance to KRAS inhibitor drugs. Using advanced methods to analyze cellular signaling, the researchers showed that ERK controls the expression of thousands of genes and alters the activity of thousands of proteins. These findings were validated in cancer models and shown to accurately predict responses in patients undergoing ERK and KRAS therapies for pancreatic, colorectal, and lung cancers.

Currently, two drugs targeting KRAS have been approved for cancer treatment, with many more under clinical evaluation. In related research published in Nature, Der and his team studied a promising anti-KRAS drug effective against numerous KRAS mutations. They discovered that the MYC oncogene contributes to resistance against KRAS therapies. The new Science papers further establish that MYC is a crucial component in how KRAS and ERK promote cancer growth and resistance to treatments.

"Our future research will focus on exploring more fundamental aspects of KRAS," said Der. "We aim to expand our scientific understanding to advance the development of more effective KRAS inhibitors."

In summary, the comprehensive molecular portrait developed by the researchers offers crucial insights into how KRAS drives pancreatic cancer. Understanding the role of ERK and MYC in this process opens new avenues for targeted therapies, potentially improving the prognosis for patients with this deadly disease. The findings underscore the importance of personalized medicine, allowing for treatments tailored to the specific molecular characteristics of each patient's cancer.