KRAS (pronounced "KAY-raz") stands for Kirsten Rat Sarcoma viral oncogene homolog, a gene that helps regulate cell growth. When KRAS is mutated, it can get stuck in the “on” position, causing cells to grow uncontrollably and form cancer. KRAS is one of the most common genetic drivers of lung cancer, found in approximately 25% of non-small cell lung cancers. For many years, KRAS was considered "undruggable," meaning researchers were unable to develop medicines that could directly target it. Today, advances in precision medicine and comprehensive biomarker testing can identify specific KRAS mutations and help connect some patients with targeted therapies that offer new treatment options.
We spoke with two KRAS American Lung Association researchers about how the KRAS gene could change cancer treatment for all.
KRAS Research and Lung Cancer Treatment
“The biggest misconception was that KRAS had no weak spots that drugs could target,” explained David Shackelford, PhD, a Lung Association grant recipient and cancer researcher at UCLA. KRAS’ smooth surface and tight hold onto GTP and GDP molecules meant drugs had little space to bind to the protein. But in 2013, researchers found that a specific KRAS mutation called G12C could be targeted after all.
"The first generation KRAS inhibitors targeted the KRAS G12C mutation, which is the most prevalent KRAS mutation in non-small cell lung cancer," continued another Lung Association grant recipient and molecular researcher Alex Jaeger, PhD. Thus, lung cancer became an important testing ground for drugs that target KRAS. "These early small molecules laid the foundation for developing sotorasib, the first KRAS inhibitor, approved by the Food and Drug Administration (FDA)."
How KRAS Research Has Evolved
The first KRAS drugs showed that this once “undruggable” target could be treated. This transformed treatment options for some patients and sparked a wave of research focused on developing treatments for other KRAS mutations and other cancers driven by the broader RAS family of genes. This was especially important for pancreatic cancer, where KRAS alterations are present in most pancreatic adenocarcinomas. In fact, "while lung cancers are more varied and may rely on other pathways, about 95% of pancreatic cancers have KRAS mutations, making them highly dependent on KRAS," Dr. Shackelford revealed. But the mutations are often different from the G12C mutation targeted by the first KRAS drugs developed for lung cancer.
"Even when two cancers have a KRAS mutation, they are not exactly the same disease," said Dr. Shackelford. "Other genetic changes in the tumor can influence how the cancer grows and responds to treatment. Lung cancer and pancreatic cancer often have different combinations of mutations. The environment around the tumor also matters.”
"It is also important to consider how tissues are exposed to different carcinogens to drive alternative mutation frequencies," added Dr. Jaeger. In other words, consider how different exposures may help explain why KRAS mutations vary between cancers.
Insight from KRAS Researchers
Both Dr. Shackelford and Dr. Jaeger are studying important questions about KRAS research in the hopes of creating even more effective treatments for cancer patients in the future.
Dr. Shackelford and his research team at UCLA study how cancer cells change their metabolism and energy production systems when they become resistant to treatment. Most recently, his team has focused their efforts on discovering why some cancers become resistant to FDA-approved KRAS-targeted drugs and newer multi-selective RAS inhibitors. "Our goal is to better understand resistance and help develop more effective treatments in the future," he said.
Dr. Jaeger and his research team at Moffitt Cancer Center have focused their research on T cells, which are cells that find and destroy cancer. Because T cells become more active after KRAS is blocked, Dr. Jaeger's team wanted to find out whether KRAS inhibitors cause cancer cells to display new antigens that the immune system can recognize. "Using advanced technology called mass spectrometry, we have now identified numerous antigens that were observed only following KRAS inhibition," he explained.
"We have also confirmed that T cells can recognize many of these new targets and are now testing whether combining KRAS inhibitors with immunotherapies, such as cancer vaccines targeting treatment induced antigens, can create a stronger attack against cancer."
The Future of Cancer Treatment
The recent FDA approval of KRAS targeted therapy for pancreatic cancer, as well as previously for lung cancer, proves that continuing research is essential to finding a cure for cancer. Just five years ago, patients with pancreatic cancer had no targeted treatment options. Now, patients with a KRAS-mutant advanced pancreatic cancer have access to daraxonrasib. In a recent clinical trial, patients receiving daraxonrasib had an increased median overall survival rate of 13.2 months as compared to 6.6 months for patients receiving chemotherapy. This offers new hope for patients with advanced disease.
"What makes this a new generation of targeted therapy is that it can target several KRAS mutations instead of only one specific mutation, such as G12C. This means more patients with KRAS-driven cancers may be able to benefit from treatment," Dr. Shackelford concluded.
"Since mutant KRAS is one of the most common oncogenic drivers across all cancers, the development of targeted therapies that effectively inhibit KRAS directly is incredibly encouraging for patients," Dr. Jaeger agreed excitedly.
Learn more about the cancer research and clinical trials we support at Lung.org/research.
Blog last updated: October 5, 2026
