K-RAS Gene Mutation

A mutation in the KRAS gene is one of the most frequently found genetic changes in cancer, affecting how cells grow and divide. Understanding this mutation can help guide treatment decisions for many patients with cancer.

Table of contents

• What is the KRAS Gene?
• How KRAS Mutations Develop
• Cancers Affected by KRAS Mutations
• Testing for KRAS Mutations
• How KRAS Mutations Affect Treatment
• KRAS-Targeted Treatments

What is the KRAS Gene?

The KRAS gene provides instructions for making a protein called K-Ras that plays an important role in controlling how cells grow and divide. This protein is part of a signaling pathway (a series of chemical signals inside a cell) known as the RAS/MAPK pathway. The K-Ras protein relays signals from outside the cell to the cell’s nucleus, instructing the cell to grow and divide or to mature and take on specialized functions.^[1]

The K-Ras protein works like an on-off switch. To transmit signals, it must be turned on by attaching to a molecule called GTP. The protein is turned off when it converts GTP to another molecule called GDP. When bound to GDP, it does not relay signals to the cell’s nucleus.^[1]

The KRAS gene belongs to a class of genes known as oncogenes (genes that, when mutated, have the potential to cause normal cells to become cancerous). The KRAS gene is part of the RAS family of oncogenes, which also includes HRAS and NRAS.^[1]

How KRAS Mutations Develop

When the KRAS gene is mutated, the K-Ras protein can become stuck in the “on” position, causing uncontrolled cancer cell growth and division. These mutations disrupt the normal on-off switch mechanism, leading to a protein that is constantly activated and continuously directing cells to grow, which can result in tumor formation.^[1][6]

KRAS gene mutations found in most cancers are somatic mutations, which means they are acquired during a person’s lifetime and are present only in tumor cells. Somatic mutations are not inherited from parents and cannot be passed on to children.^[1][8]

The vast majority of KRAS mutations are single-base changes in the DNA that commonly occur at specific positions in the gene, particularly at codons 12, 13, or 61. The most common subtypes include G12C, G12V, and G12D mutations.^[4][6]

Cancers Affected by KRAS Mutations

KRAS is one of the most commonly mutated oncogenes in solid tumors. Scientists have found that around 30 percent of all solid tumors have mutated KRAS genes.^[4][16]

The frequency of KRAS mutations varies by cancer type:

• More than 90 percent of pancreatic ductal adenocarcinomas have a KRAS mutation^[16]
• About 45 percent of colorectal cancers have a KRAS mutation^[5]
• Approximately 15 to 25 percent of non-small cell lung cancers have a KRAS mutation^[3][8]
• KRAS mutations also occur in cholangiocarcinoma and other cancer types^[1]

In lung cancer, KRAS gene mutations are more frequent in white populations than in Asian populations. About 25 to 50 percent of whites with lung cancer have KRAS gene mutations, while 5 to 15 percent of Asians with lung cancer have these mutations. These mutations appear to be more common in people who have smoked or who have been exposed to asbestos.^[8]

Testing for KRAS Mutations

Testing for KRAS mutations is performed using biomarker testing (also called molecular profiling, tumor testing, or genomic testing), which examines the genetic makeup of cancer cells. All patients with stage IV or metastatic colorectal cancer should have KRAS biomarker testing.^[5]

The recommended method of testing KRAS uses a tumor biopsy (a small tissue sample), either from the primary tumor or from a metastatic tumor. KRAS may also be tested in a blood sample by examining circulating tumor DNA, which is called a liquid biopsy. The test may be performed individually or as part of a multi-gene panel using next-generation sequencing.^[5]

If your KRAS test result is reported as “KRAS wild-type” or “KRAS WT,” this means there is no KRAS mutation in your cancer. If there is a KRAS mutation in your cancer, it will be reported as “KRAS mutant” or its specific mutation will be listed, such as “KRAS G12C” or “KRAS G12V.”^[5]

Many patients with lung cancer who test positive for the KRAS biomarker don’t have any signs or symptoms in the early stages, which is why many lung cancer patients are not diagnosed until the cancer is advanced.^[8]

How KRAS Mutations Affect Treatment

KRAS mutations affect both prognosis and treatment options. The mutation provides information about the usual course of disease and predicts which treatments may be more or less effective against a particular cancer.^[5]

For colorectal cancer, if your KRAS is wild-type (no mutation), you may benefit from targeted treatment with EGFR inhibitors (drugs that block a protein called epidermal growth factor receptor), such as cetuximab or panitumumab. KRAS wild-type colorectal cancers are sensitive to EGFR inhibitors. However, if your colorectal cancer has a KRAS mutation, EGFR inhibitors will not be effective.^[5]

Traditionally, chemotherapy has been used for patients with KRAS-mutant cancers. With the development of immunotherapy in recent years, treatment strategies have expanded to include combinations of chemotherapy and immunotherapy.^[4]

The presence of a KRAS mutation has historically been associated with poorer prognosis and treatment resistance. For decades, KRAS mutations were considered “undruggable,” meaning there was no effective way to target them with treatments.^[4][16]

KRAS-Targeted Treatments

After decades of research, scientists have made breakthrough discoveries in developing drugs that can directly target KRAS mutations. The recent development of drugs targeting the KRAS G12C mutation represents a major advancement in cancer treatment.^[6]

Two KRAS G12C inhibitors have been approved by the U.S. Food and Drug Administration:

• Sotorasib (also known as Lumakras or AMG510) was approved in 2021 for adult patients with KRAS G12C mutated locally advanced or metastatic non-small cell lung cancer^[4][10]
• Adagrasib (also known as MRTX849) was approved in 2022 for adult patients with KRAS G12C mutated locally advanced or metastatic non-small cell lung cancer. Adagrasib plus cetuximab was also approved for adults with KRAS G12C mutated locally advanced or metastatic colorectal cancer^[4]

These drugs work by binding to the mutant KRAS protein when it is in the inactive state, preventing it from sending growth signals to cancer cells.^[10]

Scientists are actively working on developing inhibitors that target other KRAS mutations beyond G12C, such as G12V and G12D. These treatments are currently being tested in clinical trials.^[6]

Research has shown that cancer cells can develop resistance to KRAS inhibitors over time. To address this challenge, scientists are exploring combination therapies that use KRAS inhibitors together with other treatments, including immunotherapy. Some studies have found innovative approaches where KRAS-targeted drugs can also help the immune system recognize and attack cancer cells.^[10]